JP2018537400A5 - - Google Patents

Description

  All publications mentioned in this specification are herein incorporated by reference to disclose and describe the methods and / or materials with which the publications are cited in relation thereto.
In certain embodiments, for example, the following are provided:
(Item 1)
CD4 binds to lymphocyte activation gene 3 (LAG-3) and is induced by antigen ⁺ T cells and / or CD8 ⁺ CD4 induced by T cell proliferation or antigen ⁺ T cells and / or CD8 ⁺ An isolated antibody or antigen-binding fragment thereof that inhibits T cell activation.
(Item 2)
CD4 induced by antigen ⁺ CD8 induced by T cells and antigens ⁺ Item 2. The isolated antibody or antigen-binding fragment thereof according to item 1, which inhibits T cell proliferation.
(Item 3)
CD8 induced by antigen ⁺ CD4 induced T-cell proliferation by antigen ⁺ 3. The isolated antibody or antigen-binding fragment thereof according to item 1 or 2, which inhibits more strongly than T cell proliferation.
(Item 4)
CD8 induced by antigen ⁺ The isolated antibody or antigen-binding fragment thereof according to any preceding item, wherein said inhibition of T cell proliferation is LAG-3-dependent and IL-2 independent.
(Item 5)
CD4 induced by antigen ⁺ T cells and / or CD8 ⁺ T cell proliferation as well as antigen induced CD4 ⁺ T cells and / or CD8 ⁺ The isolated antibody or antigen-binding fragment thereof according to any one of the preceding items, which inhibits T cell activation.
(Item 6)
CD4 binds to lymphocyte activation gene 3 (LAG-3) and is induced by antigen ⁺ T cells and / or CD8 ⁺ An isolated antibody or antigen-binding fragment thereof that inhibits T cell activation.
(Item 7)
The isolated antibody or antigen-binding fragment thereof according to any of the preceding items, which binds to LAG-3 with an affinity greater than that of monoclonal antibody 17B4.
(Item 8)
The isolated antibody or antigen-binding fragment thereof according to any one of the preceding items, which inhibits the binding of LAG-3 or IMP321 to MHC class II positive cells.
(Item 9)
The isolated antibody or antigen-binding fragment thereof according to any one of the preceding items, which inhibits activation of antigen-presenting cells (APC) induced by LAG-3 or activation of monocytes induced by IMP321 .
(Item 10)
An isolated antibody or antigen-binding fragment thereof according to any preceding item, which binds to an epitope of LAG-3 that overlaps with an MHC class II binding site of LAG-3.
(Item 11)
One, two, or three complementarity determining regions (CDRs) of an antibody heavy chain variable (VH) region comprising the amino acid sequence of SEQ ID NO: 7, and / or an antibody light chain variable comprising the amino acid sequence of SEQ ID NO: 8 An isolated antibody or antigen-binding fragment thereof according to any preceding item, comprising one, two or three CDRs of the (VL) region.
(Item 12)
The CDR of the antibody VH region is selected from the CDRs of the amino acid sequences of SEQ ID NOs: 1, 2, 3, 21, 22, and 23, and the CDRs of the antibody VL region are SEQ ID NOs: 4, 5, 6, 24, 25 The isolated antibody or antigen-binding fragment thereof according to item 11, selected from CDRs of amino acid sequences of 26 and 26.
(Item 13)
An antibody VH region comprising VH CDR1, VH CDR2, and VH CDR3,
13. The isolated antibody or antigen-binding fragment thereof according to item 11 or 12, wherein the VH CDR1 has an amino acid sequence selected from SEQ ID NOs: 1 and 21, and / or the VH CDR2 is SEQ ID NO: An isolated antibody or antigen-binding fragment thereof, having an amino acid sequence selected from 2 and 22, and / or wherein the VH CDR3 has an amino acid sequence selected from SEQ ID NOs: 3 and 23.
(Item 14)
Whether the VH CDR1 has an amino acid sequence selected from SEQ ID NOs: 1 and 21, and the VH CDR2 has an amino acid sequence selected from SEQ ID NOs: 2 and 22;
Whether the VH CDR1 has an amino acid sequence selected from SEQ ID NOs: 1 and 21, and the VH CDR3 has an amino acid sequence selected from SEQ ID NOs: 3 and 23;
The VH CDR2 has an amino acid sequence selected from SEQ ID NOs: 2 and 22, and the VH CDR3 has an amino acid sequence selected from SEQ ID NOs: 3 and 23; or
The VH CDR1 has an amino acid sequence selected from SEQ ID NOs: 1 and 21, the VH CDR2 has an amino acid sequence selected from SEQ ID NOs: 2 and 22, and the VH CDR3 has SEQ ID NOs: 3 and 23 Having an amino acid sequence selected from
Item 14. The isolated antibody or antigen-binding fragment thereof according to item 13.
(Item 15)
15. The isolated antibody or antigen-binding fragment thereof according to any of items 11 to 14, comprising an antibody VL region comprising VL CDR1, VL CDR2, and VL CDR3, wherein the VL CDR1 comprises SEQ ID NOs: 4 and 24. And / or the VL CDR2 has an amino acid sequence selected from SEQ ID NOs: 5 and 25 and / or the VL CDR3 is selected from SEQ ID NOs: 6 and 26 An isolated antibody or antigen-binding fragment thereof having an amino acid sequence.
(Item 16)
Whether the VL CDR1 has an amino acid sequence selected from SEQ ID NOs: 4 and 24, and the VL CDR2 has an amino acid sequence selected from SEQ ID NOs: 5 and 25;
Whether the VL CDR1 has an amino acid sequence selected from SEQ ID NOs: 4 and 24, and the VL CDR3 has an amino acid sequence selected from SEQ ID NOs: 6 and 26;
The VL CDR2 has an amino acid sequence selected from SEQ ID NOs: 5 and 25, and the VL CDR3 has an amino acid sequence selected from SEQ ID NOs: 6 and 26; or
The VL CDR1 has an amino acid sequence selected from SEQ ID NOs: 4 and 24, the VL CDR2 has an amino acid sequence selected from SEQ ID NOs: 5 and 25, and the VL CDR3 has SEQ ID NOs: 6 and 26 Having an amino acid sequence selected from
Item 16. The isolated antibody or antigen-binding fragment thereof according to item 15.
(Item 17)
The VH CDR1 has an amino acid sequence selected from SEQ ID NOs: 1 and 21, the VH CDR2 has an amino acid sequence selected from SEQ ID NOs: 2 and 22, and the VH CDR3 has SEQ ID NOs: 3 and 23 And / or the VL CDR1 has an amino acid sequence selected from SEQ ID NOs: 4 and 24, and the VL CDR2 has an amino acid sequence selected from SEQ ID NOs: 5 and 25 The isolated antibody or the antigen-binding fragment thereof according to any of items 13 to 16, wherein the isolated antibody has an amino acid sequence selected from SEQ ID NOs: 6 and 26.
(Item 18)
Item 11 wherein the CDR of the antibody VH region is the CDR of the amino acid sequence of SEQ ID NOs: 1, 2, and 3, and the CDR of the antibody VL region is the CDR of the amino acid sequence of SEQ ID NOs: 4, 5, and 6. 18. The isolated antibody or antigen-binding fragment thereof according to any one of 1 to 17.
(Item 19)
The CDR of the antibody VH region is the CDR of the amino acid sequence of SEQ ID NOs: 21, 22, and 23, and the CDR of the antibody VL region is the CDR of the amino acid sequence of SEQ ID NOs: 24, 25, and 26. 18. The isolated antibody or antigen-binding fragment thereof according to any one of 1 to 17.
(Item 20)
Any of the preceding, comprising an antibody VH region having a CDR comprising the amino acid sequence of SEQ ID NO: 1, 2, and 3 and / or an antibody VL region having a CDR comprising the amino acid sequence of SEQ ID NO: 4, 5, and 6 The isolated antibody or antigen-binding fragment thereof according to item.
(Item 21)
Item 1-19, comprising an antibody VH region having a CDR comprising the amino acid sequences of SEQ ID NOs: 21, 22, and 23 and / or an antibody VL region having a CDR comprising the amino acid sequences of SEQ ID NOs: 24, 25, and 26 The isolated antibody or antigen-binding fragment thereof according to any one of the above.
(Item 22)
(A) SEQ ID NO: 1, or VH CDR1 region comprising 1, 2, 3, 4, or 5 amino acid substitutions, deletions or additions compared to SEQ ID NO: 1; (b) SEQ ID NO: 2 or a VH CDR2 region comprising 1, 2, 3, 4, or 5 amino acid substitutions, deletions or additions compared to SEQ ID NO: 2; and (c) SEQ ID NO: 3, or a heavy chain variable region comprising a VH CDR3 region comprising 1, 2, 3, 4, or 5 amino acid substitutions, deletions or additions compared to SEQ ID NO: 3; and / or Or (a) VL CDR1 region comprising SEQ ID NO: 4 or 1, 2, 3, 4, or 5 amino acid substitutions, deletions or additions compared to SEQ ID NO: 4 (B) SEQ ID NO: 5, or a VL CDR2 region comprising 1, 2, 3, 4, or 5 amino acid substitutions, deletions or additions compared to SEQ ID NO: 5; and ( c) Light chain variable comprising a VL CDR3 region comprising SEQ ID NO: 6, or an amino acid sequence having 1, 2, 3, 4, or 5 amino acid substitutions, deletions or additions compared to SEQ ID NO: 6. An isolated antibody or antigen-binding fragment thereof according to any preceding item, comprising a region.
(Item 23)
(A) SEQ ID NO: 21, or a VH CDR1 region comprising 1, 2, 3, 4, or 5 amino acid substitutions, deletions or additions compared to SEQ ID NO: 21; (b) SEQ ID NO: 22 or a VH CDR2 region comprising 1, 2, 3, 4, or 5 amino acid substitutions, deletions or additions compared to SEQ ID NO: 22; and (c) SEQ ID NO: 23, or a heavy chain variable region comprising a VH CDR3 region comprising 1, 2, 3, 4, or 5 amino acid substitutions, deletions or additions compared to SEQ ID NO: 23; and / or Or (a) SEQ ID NO: 24 or an amino acid sequence having 1, 2, 3, 4, or 5 amino acid substitutions, deletions or additions compared to SEQ ID NO: 24 L CDR1 region; (b) VL CDR2 region comprising amino acid sequence having 1, 2, 3, 4, or 5 amino acid substitutions, deletions or additions compared to SEQ ID NO: 25 or SEQ ID NO: 25 And (c) comprising SEQ ID NO: 26 or a VL CDR3 region comprising 1, 2, 3, 4, or 5 amino acid substitutions, deletions or additions compared to SEQ ID NO: 26 The isolated antibody or antigen-binding fragment thereof according to any of the preceding items, comprising a light chain variable region.
(Item 24)
An antibody VH region comprising the amino acid sequence of SEQ ID NO: 7, or an amino acid sequence that is at least 60% identical to the amino acid sequence of SEQ ID NO: 7, and / or the amino acid sequence of SEQ ID NO: 8, or the amino acid sequence of SEQ ID NO: 8, at least 60% The isolated antibody or antigen-binding fragment thereof according to any of the preceding items, comprising an antibody VL region comprising an amino acid sequence that is identical.
(Item 25)
25. Item 24, comprising an antibody VH region comprising an amino acid sequence that is at least 60% identical to the amino acid sequence of SEQ ID NO: 7, and an antibody VL region comprising an amino acid sequence that is at least 60% identical to the amino acid sequence of SEQ ID NO: 8. Isolated antibody or antigen-binding fragment thereof.
(Item 26)
25. The isolated antibody or antigen-binding fragment thereof according to item 24, comprising an antibody VH region comprising an amino acid sequence at least 60% identical to the amino acid sequence of SEQ ID NO: 7 and an antibody VL region comprising the amino acid sequence of SEQ ID NO: 8. .
(Item 27)
25. The isolated antibody or antigen-binding fragment thereof according to item 24, comprising an antibody VH region comprising the amino acid sequence of SEQ ID NO: 7 and an antibody VL region comprising an amino acid sequence that is at least 60% identical to the amino acid sequence of SEQ ID NO: 8. .
(Item 28)
25. The isolated antibody or antigen-binding fragment thereof according to item 24, comprising an antibody VH region comprising the amino acid sequence of SEQ ID NO: 7 and an antibody VL region comprising the amino acid sequence of SEQ ID NO: 8.
(Item 29)
One, two or three CDRs of the antibody VH region comprising the amino acid sequence of SEQ ID NO: 17 and / or one, two or three CDRs of the antibody VL region comprising the amino acid sequence of SEQ ID NO: 18 An isolated antibody or antigen-binding fragment thereof according to any preceding item, comprising:
(Item 30)
The CDR of the antibody VH region is selected from the CDRs of amino acid sequences of SEQ ID NOs: 11, 12, 13, 31, 32, and 33, and the CDRs of the antibody VL region are SEQ ID NOs: 14, 15, 16, 34, 35 30. The isolated antibody or antigen-binding fragment thereof according to item 29, selected from CDRs of 36 amino acid sequences.
(Item 31)
31. The isolated antibody or antigen-binding fragment thereof according to item 29 or 30, comprising an antibody VH region comprising VH CDR1, VH CDR2, and VH CDR3, wherein the VH CDR1 is selected from SEQ ID NOs: 11 and 31. And / or the VH CDR2 has an amino acid sequence selected from SEQ ID NOs: 12 and 32 and / or the VH CDR3 has an amino acid sequence selected from SEQ ID NOs: 13 and 33 An isolated antibody or antigen-binding fragment thereof.
(Item 32)
Whether the VH CDR1 has an amino acid sequence selected from SEQ ID NOs: 11 and 31, and the VH CDR2 has an amino acid sequence selected from SEQ ID NOs: 12 and 32;
Whether the VH CDR1 has an amino acid sequence selected from SEQ ID NOs: 11 and 31, and the VH CDR3 has an amino acid sequence selected from SEQ ID NOs: 13 and 33;
The VH CDR2 has an amino acid sequence selected from SEQ ID NOs: 12 and 32, and the VH CDR3 has an amino acid sequence selected from SEQ ID NOs: 13 and 33; or
The VH CDR1 has an amino acid sequence selected from SEQ ID NOs: 11 and 31, the VH CDR2 has an amino acid sequence selected from SEQ ID NOs: 12 and 32, and the VH CDR3 has SEQ ID NOs: 13 and 33. Having an amino acid sequence selected from
32. The isolated antibody or antigen-binding fragment thereof according to item 31.
(Item 33)
33. The isolated antibody or antigen-binding fragment thereof according to any of items 29 to 32, comprising an antibody VL region comprising VL CDR1, VL CDR2, and VL CDR3, wherein the VL CDR1 comprises SEQ ID NOs: 14 and 34. And / or the VL CDR2 has an amino acid sequence selected from SEQ ID NOs: 15 and 35 and / or the VL CDR3 is selected from SEQ ID NOs: 16 and 36 An isolated antibody or antigen-binding fragment thereof having an amino acid sequence.
(Item 34)
Whether the VL CDR1 has an amino acid sequence selected from SEQ ID NOs: 14 and 34, and the VL CDR2 has an amino acid sequence selected from SEQ ID NOs: 15 and 35;
Whether the VL CDR1 has an amino acid sequence selected from SEQ ID NOs: 14 and 34, and the VL CDR3 has an amino acid sequence selected from SEQ ID NOs: 16 and 36;
The VL CDR2 has an amino acid sequence selected from SEQ ID NOs: 15 and 35, and the VL CDR3 has an amino acid sequence selected from SEQ ID NOs: 16 and 36; or
The VL CDR1 has an amino acid sequence selected from SEQ ID NOs: 14 and 34, the VL CDR2 has an amino acid sequence selected from SEQ ID NOs: 15 and 35, and the VL CDR3 has SEQ ID NOs: 16 and 36 Having an amino acid sequence selected from
34. The isolated antibody or antigen-binding fragment thereof according to item 33.
(Item 35)
The VH CDR1 has an amino acid sequence selected from SEQ ID NOs: 11 and 31, the VH CDR2 has an amino acid sequence selected from SEQ ID NOs: 12 and 32, and the VH CDR3 has SEQ ID NOs: 13 and 33. And / or the VL CDR1 has an amino acid sequence selected from SEQ ID NOs: 14 and 34, and the VL CDR2 has an amino acid sequence selected from SEQ ID NOs: 15 and 35 35. The isolated antibody or the antigen-binding fragment thereof according to any one of items 31 to 34, wherein the VL CDR3 has an amino acid sequence selected from SEQ ID NOs: 16 and 36.
(Item 36)
Item 29, wherein the CDR of the antibody VH region is the CDR of the amino acid sequence of SEQ ID NOs: 11, 12, and 13, and the CDR of the antibody VL region is the CDR of the amino acid sequence of SEQ ID NOs: 14, 15, and 16. 36. The isolated antibody or antigen-binding fragment thereof according to any one of to 35.
(Item 37)
The CDR of the antibody VH region is the CDR of the amino acid sequence of SEQ ID NOs: 31, 32, and 33, and the CDR of the antibody VL region is the CDR of the amino acid sequence of SEQ ID NOs: 34, 35, and 36. 36. The isolated antibody or antigen-binding fragment thereof according to any one of to 35.
(Item 38)
Any of the preceding, comprising an antibody VH region having a CDR comprising the amino acid sequence of SEQ ID NO: 11, 12, and 13 and / or an antibody VL region having a CDR comprising the amino acid sequence of SEQ ID NO: 14, 15, and 16 The isolated antibody or antigen-binding fragment thereof according to item.
(Item 39)
Any of the preceding, comprising an antibody VH region having a CDR comprising the amino acid sequence of SEQ ID NO: 31, 32, and 33, and / or an antibody VL region having a CDR comprising the amino acid sequence of SEQ ID NO: 34, 35, and 36 The isolated antibody or antigen-binding fragment thereof according to item.
(Item 40)
(A) SEQ ID NO: 11 or a VH CDR1 region comprising 1, 2, 3, 4, or 5 amino acid substitutions, deletions or additions compared to SEQ ID NO: 11; (b) SEQ ID NO: 12, or a VH CDR2 region comprising 1, 2, 3, 4, or 5 amino acid substitutions, deletions or additions compared to SEQ ID NO: 12; and (c) SEQ ID NO: 13, or a CDR comprising an amino acid sequence having 1, 2, 3, 4, or 5 amino acid substitutions, deletions or additions compared to SEQ ID NO: 13
A heavy chain variable region comprising three regions; and / or (a) SEQ ID NO: 14, or 1, 2, 3, 4, or 5 amino acid substitutions, deletions or additions compared to SEQ ID NO: 14. A VL CDR1 region comprising an amino acid sequence having; (b) an amino acid sequence having 1, 2, 3, 4, or 5 amino acid substitutions, deletions or additions compared to SEQ ID NO: 15 or SEQ ID NO: 15; A VL CDR2 region comprising; and (c) comprising SEQ ID NO: 16, or an amino acid sequence having 1, 2, 3, 4, or 5 amino acid substitutions, deletions or additions compared to SEQ ID NO: 16 The isolated antibody or antigen-binding fragment thereof according to any of the preceding items, comprising a light chain variable region comprising a VL CDR3 region.
(Item 41)
(A) SEQ ID NO: 31 or a VH CDR1 region comprising 1, 2, 3, 4, or 5 amino acid substitutions, deletions or additions compared to SEQ ID NO: 31; (b) SEQ ID NO: 32, or a VH CDR2 region comprising 1, 2, 3, 4, or 5 amino acid substitutions, deletions or additions compared to SEQ ID NO: 32; and (c) SEQ ID NO: 33, or a heavy chain variable region comprising a CDR3 region comprising an amino acid sequence having 1, 2, 3, 4, or 5 amino acid substitutions, deletions or additions compared to SEQ ID NO: 33; and / or (A) VL comprising SEQ ID NO: 34 or an amino acid sequence having 1, 2, 3, 4, or 5 amino acid substitutions, deletions or additions compared to SEQ ID NO: 34 DR1 region; (b) VL CDR2 region comprising amino acid sequence having 1, 2, 3, 4, or 5 amino acid substitutions, deletions or additions compared to SEQ ID NO: 35 or SEQ ID NO: 35; And (c) SEQ ID NO: 36, or a lighter comprising a VL CDR3 region comprising 1, 2, 3, 4, or 5 amino acid substitutions, deletions or additions compared to SEQ ID NO: 36. The isolated antibody or antigen-binding fragment thereof according to any one of the preceding items, comprising a chain variable region.
(Item 42)
An antibody VH region comprising the amino acid sequence of SEQ ID NO: 17, or an amino acid sequence that is at least 60% identical to the amino acid sequence of SEQ ID NO: 17, and / or the amino acid sequence of SEQ ID NO: 18, or at least 60% with the amino acid sequence of SEQ ID NO: 18 The isolated antibody or antigen-binding fragment thereof according to any of the preceding items, comprising an antibody VL region comprising an amino acid sequence that is identical.
(Item 43)
45. Item 42, comprising an antibody VH region comprising an amino acid sequence that is at least 60% identical to the amino acid sequence of SEQ ID NO: 17, and an antibody VL region comprising an amino acid sequence that is at least 60% identical to the amino acid sequence of SEQ ID NO: 18. Isolated antibody or antigen-binding fragment thereof.
(Item 44)
45. The isolated antibody or antigen-binding fragment thereof according to item 42, comprising an antibody VH region comprising an amino acid sequence that is at least 60% identical to the amino acid sequence of SEQ ID NO: 17, and an antibody VL region comprising the amino acid sequence of SEQ ID NO: 18. .
(Item 45)
45. The isolated antibody or antigen-binding fragment thereof according to item 42, comprising an antibody VH region comprising the amino acid sequence of SEQ ID NO: 17 and an antibody VL region comprising an amino acid sequence that is at least 60% identical to the amino acid sequence of SEQ ID NO: 18. .
(Item 46)
43. The isolated antibody or antigen-binding fragment thereof according to item 42, comprising an antibody VH region comprising the amino acid sequence of SEQ ID NO: 17 and an antibody VL region comprising the amino acid sequence of SEQ ID NO: 18.
(Item 47)
The isolated antibody or antigen-binding fragment thereof according to any preceding item, which is a humanized monoclonal antibody or antigen-binding fragment thereof.
(Item 48)
The isolated antibody or antigen-binding fragment thereof according to any of the preceding items, comprising a humanized light chain framework region.
(Item 49)
The humanized light chain framework region is VL ₁ , VL ₂ , VL ₃ Or VL ₄ 49. The isolated antibody or antigen-binding fragment thereof of item 48, comprising an amino acid sequence having any of the amino acid substitutions shown in Table 27 for.
(Item 50)
50. The isolated antibody or antigen-binding fragment thereof according to item 48 or 49, wherein the humanized light chain framework region comprises any one of the amino acid sequences of SEQ ID NOs: 68 to 83.
(Item 51)
VL framework region 1 of SEQ ID NO: 68 (VL FR1); VL FR2 of SEQ ID NO: 69; VL FR3 of SEQ ID NO: 70; and VL FR4 of SEQ ID NO: 71;
VL framework region 1 of SEQ ID NO: 72 (VL FR1); VL FR2 of SEQ ID NO: 73; VL FR3 of SEQ ID NO: 74; and VL FR4 of SEQ ID NO: 75;
VL framework region 1 of SEQ ID NO: 76 (VL FR1); VL FR2 of SEQ ID NO: 77; VL FR3 of SEQ ID NO: 78; and VL FR4 of SEQ ID NO: 79; or
VL framework region 1 of SEQ ID NO: 80 (VL FR1); VL FR2 of SEQ ID NO: 81; VL FR3 of SEQ ID NO: 82; and VL FR4 of SEQ ID NO: 83
The isolated antibody or antigen-binding fragment thereof according to item 50, comprising:
(Item 52)
VL FR1 having an amino acid sequence of SEQ ID NO: 68; VL CDR1 having an amino acid sequence selected from SEQ ID NOs: 4 and 24; VL FR2 having an amino acid sequence of SEQ ID NO: 69; and an amino acid sequence selected from SEQ ID NOs: 5 and 25 A VL CDR2 having an amino acid sequence of SEQ ID NO: 70; a VL CDR3 having an amino acid sequence selected from SEQ ID NOs: 6 and 26; and a VL FR4 having an amino acid sequence of SEQ ID NO: 71
52. The isolated antibody or antigen-binding fragment thereof according to any of items 48 to 51, comprising an antibody VL region comprising
(Item 53)
VL FR1 having the amino acid sequence of SEQ ID NO: 68; VL CDR1 having the amino acid sequence of SEQ ID NO: 4; VL FR2 having the amino acid sequence of SEQ ID NO: 69; VL CDR2 having the amino acid sequence of SEQ ID NO: 5; VL FR3 having the amino acid sequence of SEQ ID NO: 6; and VL FR4 having the amino acid sequence of SEQ ID NO: 71
52. The isolated antibody or antigen-binding fragment thereof according to any of items 48 to 51, comprising an antibody VL region comprising
(Item 54)
VL FR1 having the amino acid sequence of SEQ ID NO: 68; VL CDR1 having the amino acid sequence of SEQ ID NO: 24; VL FR2 having the amino acid sequence of SEQ ID NO: 69; VL CDR2 having the amino acid sequence of SEQ ID NO: 25; VL FR3 having the amino acid sequence of SEQ ID NO: 26; and VL FR4 having the amino acid sequence of SEQ ID NO: 71
52. The isolated antibody or antigen-binding fragment thereof according to any of items 48 to 51, comprising an antibody VL region comprising
(Item 55)
VL FR1 having an amino acid sequence of SEQ ID NO: 72; VL CDR1 having an amino acid sequence selected from SEQ ID NOs: 4 and 24; VL FR2 having an amino acid sequence of SEQ ID NO: 73; and an amino acid sequence selected from SEQ ID NOs: 5 and 25 A VL CDR2 having an amino acid sequence of SEQ ID NO: 74; a VL CDR3 having an amino acid sequence selected from SEQ ID NOs: 6 and 26; and a VL FR4 having an amino acid sequence of SEQ ID NO: 75
52. The isolated antibody or antigen-binding fragment thereof according to any of items 48 to 51, comprising an antibody VL region comprising
(Item 56)
VL FR1 having the amino acid sequence of SEQ ID NO: 72; VL CDR1 having the amino acid sequence of SEQ ID NO: 4; VL FR2 having the amino acid sequence of SEQ ID NO: 73; VL CDR2 having the amino acid sequence of SEQ ID NO: 5; VL FR3 having the amino acid sequence of SEQ ID NO: 6; and VL FR4 having the amino acid sequence of SEQ ID NO: 75
52. The isolated antibody or antigen-binding fragment thereof according to any of items 48 to 51, comprising an antibody VL region comprising
(Item 57)
VL FR1 having the amino acid sequence of SEQ ID NO: 72; VL CDR1 having the amino acid sequence of SEQ ID NO: 24; VL FR2 having the amino acid sequence of SEQ ID NO: 73; VL CDR2 having the amino acid sequence of SEQ ID NO: 25; VL FR3 having the amino acid sequence of SEQ ID NO: 26; and VL FR4 having the amino acid sequence of SEQ ID NO: 75
52. The isolated antibody or antigen-binding fragment thereof according to any of items 48 to 51, comprising an antibody VL region comprising
(Item 58)
VL FR1 having an amino acid sequence of SEQ ID NO: 76; VL CDR1 having an amino acid sequence selected from SEQ ID NOs: 4 and 24; VL FR2 having an amino acid sequence of SEQ ID NO: 77; and an amino acid sequence selected from SEQ ID NOs: 5 and 25 VL CDR2 having the amino acid sequence of SEQ ID NO: 78; VL CDR3 having an amino acid sequence selected from SEQ ID NOs: 6 and 26; and VL FR4 having the amino acid sequence of SEQ ID NO: 79
52. The isolated antibody or antigen-binding fragment thereof according to any of items 48 to 51, comprising an antibody VL region comprising
(Item 59)
VL FR1 having the amino acid sequence of SEQ ID NO: 76; VL CDR1 having the amino acid sequence of SEQ ID NO: 4; VL FR2 having the amino acid sequence of SEQ ID NO: 77; VL CDR2 having the amino acid sequence of SEQ ID NO: 5; VL FR3 having the amino acid sequence of SEQ ID NO: 6; and VL FR4 having the amino acid sequence of SEQ ID NO: 79
52. The isolated antibody or antigen-binding fragment thereof according to any of items 48 to 51, comprising an antibody VL region comprising
(Item 60)
VL FR1 having the amino acid sequence of SEQ ID NO: 76; VL CDR1 having the amino acid sequence of SEQ ID NO: 24; VL FR2 having the amino acid sequence of SEQ ID NO: 77; VL CDR2 having the amino acid sequence of SEQ ID NO: 25; VL FR3 having the amino acid sequence of SEQ ID NO: 26; and VL FR4 having the amino acid sequence of SEQ ID NO: 79
52. The isolated antibody or antigen-binding fragment thereof according to any of items 48 to 51, comprising an antibody VL region comprising
(Item 61)
VL FR1 having an amino acid sequence of SEQ ID NO: 80; VL CDR1 having an amino acid sequence selected from SEQ ID NOs: 4 and 24; VL FR2 having an amino acid sequence of SEQ ID NO: 81; and an amino acid sequence selected from SEQ ID NOs: 5 and 25 A VL CDR2 having an amino acid sequence of SEQ ID NO: 82; a VL CDR3 having an amino acid sequence selected from SEQ ID NOs: 6 and 26; and a VL FR4 having an amino acid sequence of SEQ ID NO: 83
52. The isolated antibody or antigen-binding fragment thereof according to any of items 48 to 51, comprising an antibody VL region comprising
(Item 62)
VL FR1 having the amino acid sequence of SEQ ID NO: 80; VL CDR1 having the amino acid sequence of SEQ ID NO: 4; VL FR2 having the amino acid sequence of SEQ ID NO: 81; VL CDR2 having the amino acid sequence of SEQ ID NO: 5; A VL FR3 having an amino acid sequence selected from SEQ ID NO: 6; and a VL FR4 having an amino acid sequence of SEQ ID NO: 83
52. The isolated antibody or antigen-binding fragment thereof according to any of items 48 to 51, comprising an antibody VL region comprising
(Item 63)
VL FR1 having the amino acid sequence of SEQ ID NO: 80; VL CDR1 having the amino acid sequence of SEQ ID NO: 24; VL FR2 having the amino acid sequence of SEQ ID NO: 81; VL CDR2 having the amino acid sequence selected from SEQ ID NO: 25; SEQ ID NO: 82 VL FR3 having an amino acid sequence of: VL CDR3 having an amino acid sequence selected from SEQ ID NO: 26; and VL FR4 having an amino acid sequence of SEQ ID NO: 83
52. The isolated antibody or antigen-binding fragment thereof according to any of items 48 to 51, comprising an antibody VL region comprising
(Item 64)
VL FR1 having the amino acid sequence of SEQ ID NO: 68; VL CDR1 having an amino acid sequence selected from SEQ ID NOs: 14 and 34; VL having the amino acid sequence of SEQ ID NO: 69
FR2; VL CDR2 having an amino acid sequence selected from SEQ ID NOs: 15 and 35; VL FR3 having an amino acid sequence of SEQ ID NO: 70; VL CDR3 having an amino acid sequence selected from SEQ ID NOs: 16 and 36; VL FR4 having amino acid sequence
52. The isolated antibody or antigen-binding fragment thereof according to any of items 48 to 51, comprising an antibody VL region comprising
(Item 65)
VL FR1 having the amino acid sequence of SEQ ID NO: 68; VL CDR1 having the amino acid sequence of SEQ ID NO: 14; VL FR2 having the amino acid sequence of SEQ ID NO: 69; VL CDR2 having the amino acid sequence of SEQ ID NO: 15; VL FR3 having the amino acid sequence of SEQ ID NO: 16; and VL FR4 having the amino acid sequence of SEQ ID NO: 71
52. The isolated antibody or antigen-binding fragment thereof according to any of items 48 to 51, comprising an antibody VL region comprising
(Item 66)
VL FR1 having the amino acid sequence of SEQ ID NO: 68; VL CDR1 having the amino acid sequence of SEQ ID NO: 34; VL FR2 having the amino acid sequence of SEQ ID NO: 69; VL CDR2 having the amino acid sequence of SEQ ID NO: 35; VL FR3 having the amino acid sequence of SEQ ID NO: 36; and VL FR4 having the amino acid sequence of SEQ ID NO: 71
52. The isolated antibody or antigen-binding fragment thereof according to any of items 48 to 51, comprising an antibody VL region comprising
(Item 67)
A VL FR1 having the amino acid sequence of SEQ ID NO: 72; a VL CDR1 having an amino acid sequence selected from SEQ ID NOs: 14 and 34; a VL FR2 having an amino acid sequence of SEQ ID NO: 73; an amino acid sequence selected from SEQ ID NOs: 15 and 35 A VL CDR2 having an amino acid sequence of SEQ ID NO: 74; a VL CDR3 having an amino acid sequence selected from SEQ ID NOs: 16 and 36; and a VL FR4 having an amino acid sequence of SEQ ID NO: 75
52. The isolated antibody according to any one of items 48 to 51, which comprises an antibody VL region comprising
Antigen binding fragment.
(Item 68)
VL FR1 having the amino acid sequence of SEQ ID NO: 72; VL CDR1 having the amino acid sequence of SEQ ID NO: 14; VL FR2 having the amino acid sequence of SEQ ID NO: 73; VL CDR2 having the amino acid sequence of SEQ ID NO: 15; VL FR3 having the amino acid sequence of SEQ ID NO: 16; and VL FR4 having the amino acid sequence of SEQ ID NO: 75
52. The isolated antibody or antigen-binding fragment thereof according to any of items 48 to 51, comprising an antibody VL region comprising
(Item 69)
VL FR1 having the amino acid sequence of SEQ ID NO: 72; VL CDR1 having the amino acid sequence of SEQ ID NO: 34; VL FR2 having the amino acid sequence of SEQ ID NO: 73; VL CDR2 having the amino acid sequence of SEQ ID NO: 35; VL FR3 having the amino acid sequence of SEQ ID NO: 36; and VL FR4 having the amino acid sequence of SEQ ID NO: 75
52. The isolated antibody or antigen-binding fragment thereof according to any of items 48 to 51, comprising an antibody VL region comprising
(Item 70)
VL FR1 having an amino acid sequence of SEQ ID NO: 76; VL CDR1 having an amino acid sequence selected from SEQ ID NOs: 14 and 34; VL FR2 having an amino acid sequence of SEQ ID NO: 77; and an amino acid sequence selected from SEQ ID NOs: 15 and 35 A VL CDR2 having an amino acid sequence of SEQ ID NO: 78; a VL CDR3 having an amino acid sequence selected from SEQ ID NOs: 16 and 36; and a VL FR4 having an amino acid sequence of SEQ ID NO: 79
52. The isolated antibody or antigen-binding fragment thereof according to any of items 48 to 51, comprising an antibody VL region comprising
(Item 71)
VL FR1 having the amino acid sequence of SEQ ID NO: 76; VL CDR1 having the amino acid sequence of SEQ ID NO: 14; VL FR2 having the amino acid sequence of SEQ ID NO: 77; VL CDR2 having the amino acid sequence of SEQ ID NO: 15; VL FR3 having the amino acid sequence of SEQ ID NO: 16; and VL FR4 having the amino acid sequence of SEQ ID NO: 79
52. The isolated antibody or antigen-binding fragment thereof according to any of items 48 to 51, comprising an antibody VL region comprising
(Item 72)
VL FR1 having the amino acid sequence of SEQ ID NO: 76; VL CDR1 having the amino acid sequence of SEQ ID NO: 34; VL FR2 having the amino acid sequence of SEQ ID NO: 77; VL CDR2 having the amino acid sequence of SEQ ID NO: 35; VL FR3 having the amino acid sequence of SEQ ID NO: 36; and VL FR4 having the amino acid sequence of SEQ ID NO: 79
52. The isolated antibody or antigen-binding fragment thereof according to any of items 48 to 51, comprising an antibody VL region comprising
(Item 73)
VL FR1 having an amino acid sequence of SEQ ID NO: 80; VL CDR1 having an amino acid sequence selected from SEQ ID NOs: 14 and 34; VL FR2 having an amino acid sequence of SEQ ID NO: 81; and an amino acid sequence selected from SEQ ID NOs: 15 and 35 VL CDR2 having the amino acid sequence of SEQ ID NO: 82; VL CDR3 having an amino acid sequence selected from SEQ ID NOs: 16 and 36; and VL FR4 having the amino acid sequence of SEQ ID NO: 83
52. The isolated antibody or antigen-binding fragment thereof according to any of items 48 to 51, comprising an antibody VL region comprising
(Item 74)
VL FR1 having the amino acid sequence of SEQ ID NO: 80; VL CDR1 having the amino acid sequence of SEQ ID NO: 14; VL FR2 having the amino acid sequence of SEQ ID NO: 81; VL CDR2 having the amino acid sequence of SEQ ID NO: 15; VL FR3 having the amino acid sequence of SEQ ID NO: 16; and VL FR4 having the amino acid sequence of SEQ ID NO: 83
52. The isolated antibody or antigen-binding fragment thereof according to any of items 48 to 51, comprising an antibody VL region comprising
(Item 75)
VL FR1 having the amino acid sequence of SEQ ID NO: 80; VL CDR1 having the amino acid sequence of SEQ ID NO: 34; VL FR2 having the amino acid sequence of SEQ ID NO: 81; VL CDR2 having the amino acid sequence of SEQ ID NO: 35; VL FR3 having the amino acid sequence of SEQ ID NO: 36; and VL FR4 having the amino acid sequence of SEQ ID NO: 83
52. The isolated antibody or antigen-binding fragment thereof according to any of items 48 to 51, comprising an antibody VL region comprising
(Item 76)
The isolated antibody or antigen-binding fragment thereof according to any preceding item, comprising a humanized heavy chain framework region.
(Item 77)
The humanized heavy chain framework region is VH ₁ , VH ₂ , VH ₃ Or VH ₄ 77. The isolated antibody or antigen-binding fragment thereof of item 76, comprising an amino acid sequence having any of the amino acid substitutions shown in Table 26 for
(Item 78)
78. The isolated antibody or antigen-binding fragment thereof according to item 76 or 77, wherein the humanized heavy chain framework region comprises any one of the amino acid sequences of SEQ ID NOs: 52 to 67.
(Item 79)
VH framework region 1 of SEQ ID NO: 52 (VH FR1); VH FR2 of SEQ ID NO: 53; VH FR3 of SEQ ID NO: 54; and VH FR4 of SEQ ID NO: 55;
VH framework region 1 of SEQ ID NO: 56 (VH FR1); VH FR2 of SEQ ID NO: 57; VH FR3 of SEQ ID NO: 58; and VH FR4 of SEQ ID NO: 59;
VH framework region 1 of SEQ ID NO: 60 (VH FR1); VH FR2 of SEQ ID NO: 61; VH FR3 of SEQ ID NO: 62; and VH FR4 of SEQ ID NO: 63; or
VH framework region 1 of SEQ ID NO: 64 (VH FR1); VH FR2 of SEQ ID NO: 65; VH FR3 of SEQ ID NO: 66; and VH FR4 of SEQ ID NO: 67
79. The isolated antibody or antigen-binding fragment thereof according to item 78, comprising
(Item 80)
VH FR1 having an amino acid sequence of SEQ ID NO: 52; VH CDR1 having an amino acid sequence selected from SEQ ID NOs: 1 and 21; VH FR2 having an amino acid sequence of SEQ ID NO: 53; amino acid sequences selected from SEQ ID NOs: 2 and 22 VH CDR2 having VH FR3 having an amino acid sequence of SEQ ID NO: 54; VH CDR3 having an amino acid sequence selected from SEQ ID NOs: 3 and 23; and VH FR4 having an amino acid sequence of SEQ ID NO: 55
80. The isolated antibody or antigen-binding fragment thereof according to any of items 76 to 79, comprising an antibody VH region comprising
(Item 81)
VH FR1 having the amino acid sequence of SEQ ID NO: 52; VH CDR1 having the amino acid sequence of SEQ ID NO: 1; VH FR2 having the amino acid sequence of SEQ ID NO: 53; VH CDR2 having the amino acid sequence of SEQ ID NO: 2; VH FR3 having the amino acid sequence of SEQ ID NO: 3; and VH FR4 having the amino acid sequence of SEQ ID NO: 55
80. The isolated antibody or antigen-binding fragment thereof according to any of items 76 to 79, comprising an antibody VH region comprising
(Item 82)
VH FR1 having the amino acid sequence of SEQ ID NO: 52; VH CDR1 having the amino acid sequence of SEQ ID NO: 21; VH FR2 having the amino acid sequence of SEQ ID NO: 53; VH CDR2 having the amino acid sequence of SEQ ID NO: 22; VH FR3 having the amino acid sequence of SEQ ID NO: 23; and VH FR4 having the amino acid sequence of SEQ ID NO: 55
80. The isolated antibody or antigen-binding fragment thereof according to any of items 76 to 79, comprising an antibody VH region comprising
(Item 83)
VH FR1 having an amino acid sequence of SEQ ID NO: 56; VH CDR1 having an amino acid sequence selected from SEQ ID NOs: 1 and 21; VH FR2 having an amino acid sequence of SEQ ID NO: 57; and an amino acid sequence selected from SEQ ID NOs: 2 and 22 VH CDR2 having VH FR3 having an amino acid sequence of SEQ ID NO: 58; VH CDR3 having an amino acid sequence selected from SEQ ID NOs: 3 and 23; and VH FR4 having an amino acid sequence of SEQ ID NO: 59
80. The isolated antibody or antigen-binding fragment thereof according to any of items 76 to 79, comprising an antibody VH region comprising
(Item 84)
VH FR1 having the amino acid sequence of SEQ ID NO: 56; VH CDR1 having the amino acid sequence of SEQ ID NO: 1; VH FR2 having the amino acid sequence of SEQ ID NO: 57; VH CDR2 having the amino acid sequence of SEQ ID NO: 2; VH FR3 having the amino acid sequence of SEQ ID NO: 3; and VH FR4 having the amino acid sequence of SEQ ID NO: 59
80. The isolated antibody or antigen-binding fragment thereof according to any of items 76 to 79, comprising an antibody VH region comprising
(Item 85)
VH FR1 having the amino acid sequence of SEQ ID NO: 56; VH CDR1 having the amino acid sequence of SEQ ID NO: 21; VH FR2 having the amino acid sequence of SEQ ID NO: 57; VH CDR2 having the amino acid sequence of SEQ ID NO: 22; VH FR3 having the amino acid sequence of SEQ ID NO: 23; and VH FR4 having the amino acid sequence of SEQ ID NO: 59
80. The isolated antibody or antigen-binding fragment thereof according to any of items 76 to 79, comprising an antibody VH region comprising
(Item 86)
A VH FR1 having the amino acid sequence of SEQ ID NO: 60; a VH CDR1 having an amino acid sequence selected from SEQ ID NOs: 1 and 21; a VH FR2 having an amino acid sequence of SEQ ID NO: 61; and an amino acid sequence selected from SEQ ID NOs: 2 and 22 VH CDR2 having the amino acid sequence of SEQ ID NO: 62; VH CDR3 having an amino acid sequence selected from SEQ ID NOs: 3 and 23; and VH FR4 having the amino acid sequence of SEQ ID NO: 63
80. The isolated antibody or antigen-binding fragment thereof according to any of items 76 to 79, comprising an antibody VH region comprising
(Item 87)
VH FR1 having the amino acid sequence of SEQ ID NO: 60; VH CDR1 having the amino acid sequence of SEQ ID NO: 1; VH FR2 having the amino acid sequence of SEQ ID NO: 61; VH CDR2 having the amino acid sequence of SEQ ID NO: 2; VH FR3 having the amino acid sequence of SEQ ID NO: 3; and VH FR4 having the amino acid sequence of SEQ ID NO: 63
80. The isolated antibody or antigen-binding fragment thereof according to any of items 76 to 79, comprising an antibody VH region comprising
(Item 88)
VH FR1 having the amino acid sequence of SEQ ID NO: 60; VH CDR1 having the amino acid sequence of SEQ ID NO: 21; VH FR2 having the amino acid sequence of SEQ ID NO: 61; VH CDR2 having the amino acid sequence of SEQ ID NO: 22; VH FR3 having the amino acid sequence of SEQ ID NO: 23; and VH FR4 having the amino acid sequence of SEQ ID NO: 63
80. The isolated antibody or antigen-binding fragment thereof according to any of items 76 to 79, comprising an antibody VH region comprising
(Item 89)
VH FR1 having the amino acid sequence of SEQ ID NO: 64; VH CDR1 having an amino acid sequence selected from SEQ ID NO: 1 and 21; VH FR2 having the amino acid sequence of SEQ ID NO: 65; amino acid sequence selected from SEQ ID NO: 2 and 22 A VH CDR2 having an amino acid sequence of SEQ ID NO: 66; a VH CDR3 having an amino acid sequence selected from SEQ ID NOs: 3 and 23; and a VH FR4 having an amino acid sequence of SEQ ID NO: 67
80. The isolated antibody or antigen-binding fragment thereof according to any of items 76 to 79, comprising an antibody VH region comprising
(Item 90)
VH FR1 having the amino acid sequence of SEQ ID NO: 64; VH CDR1 having the amino acid sequence of SEQ ID NO: 1; VH FR2 having the amino acid sequence of SEQ ID NO: 65; VH CDR2 having the amino acid sequence of SEQ ID NO: 2; VH FR3 having the amino acid sequence of SEQ ID NO: 3; and VH FR4 having the amino acid sequence of SEQ ID NO: 67
80. The isolated antibody or antigen-binding fragment thereof according to any of items 76 to 79, comprising an antibody VH region comprising
(Item 91)
VH FR1 having the amino acid sequence of SEQ ID NO: 64; VH CDR1 having the amino acid sequence of SEQ ID NO: 21; VH FR2 having the amino acid sequence of SEQ ID NO: 65; VH CDR2 having the amino acid sequence of SEQ ID NO: 22; VH FR3 having the amino acid sequence of SEQ ID NO: 23; and VH FR4 having the amino acid sequence of SEQ ID NO: 67
80. The isolated antibody or antigen-binding fragment thereof according to any of items 76 to 79, comprising an antibody VH region comprising
(Item 92)
A VH FR1 having an amino acid sequence of SEQ ID NO: 52; a VH CDR1 having an amino acid sequence selected from SEQ ID NOs: 11 and 31; a VH FR2 having an amino acid sequence of SEQ ID NO: 53; and an amino acid sequence selected from SEQ ID NOs: 12 and 32 VH CDR2 having VH FR3 having an amino acid sequence of SEQ ID NO: 54; VH CDR3 having an amino acid sequence selected from SEQ ID NOs: 3 and 33; and VH FR4 having an amino acid sequence of SEQ ID NO: 55
80. The isolated antibody or antigen-binding fragment thereof according to any of items 76 to 79, comprising an antibody VH region comprising
(Item 93)
VH FR1 having the amino acid sequence of SEQ ID NO: 52; VH CDR1 having the amino acid sequence of SEQ ID NO: 11; VH FR2 having the amino acid sequence of SEQ ID NO: 53; VH CDR2 having the amino acid sequence of SEQ ID NO: 12; VH FR3 having the amino acid sequence of SEQ ID NO: 3; and VH FR4 having the amino acid sequence of SEQ ID NO: 55
80. The isolated antibody or antigen-binding fragment thereof according to any of items 76 to 79, comprising an antibody VH region comprising
(Item 94)
VH FR1 having the amino acid sequence of SEQ ID NO: 52; VH CDR1 having the amino acid sequence of SEQ ID NO: 31; VH FR2 having the amino acid sequence of SEQ ID NO: 53; VH CDR2 having the amino acid sequence of SEQ ID NO: 32; VH FR3 having the amino acid sequence of SEQ ID NO: 33; and VH FR4 having the amino acid sequence of SEQ ID NO: 55
80. The isolated antibody or antigen-binding fragment thereof according to any of items 76 to 79, comprising an antibody VH region comprising
(Item 95)
VH FR1 having an amino acid sequence of SEQ ID NO: 56; VH CDR1 having an amino acid sequence selected from SEQ ID NOs: 11 and 31; VH FR2 having an amino acid sequence of SEQ ID NO: 57; and an amino acid sequence selected from SEQ ID NOs: 12 and 32 VH CDR2 having the amino acid sequence of SEQ ID NO: 58; VH CDR3 having an amino acid sequence selected from SEQ ID NOs: 13 and 33; and VH FR4 having the amino acid sequence of SEQ ID NO: 59
80. The isolated antibody or antigen-binding fragment thereof according to any of items 76 to 79, comprising an antibody VH region comprising
(Item 96)
VH FR1 having the amino acid sequence of SEQ ID NO: 56; VH CDR1 having the amino acid sequence of SEQ ID NO: 11; VH FR2 having the amino acid sequence of SEQ ID NO: 57; VH CDR2 having the amino acid sequence of SEQ ID NO: 12; VH FR3 having the amino acid sequence of SEQ ID NO: 13; and VH FR4 having the amino acid sequence of SEQ ID NO: 59
80. The isolated antibody or antigen-binding fragment thereof according to any of items 76 to 79, comprising an antibody VH region comprising
(Item 97)
VH FR1 having the amino acid sequence of SEQ ID NO: 56; VH CDR1 having the amino acid sequence of SEQ ID NO: 31; VH FR2 having the amino acid sequence of SEQ ID NO: 57; VH CDR2 having the amino acid sequence of SEQ ID NO: 32; VH FR3 having the amino acid sequence of SEQ ID NO: 33; and VH FR4 having the amino acid sequence of SEQ ID NO: 59
80. The isolated antibody or antigen-binding fragment thereof according to any of items 76 to 79, comprising an antibody VH region comprising
(Item 98)
A VH FR1 having the amino acid sequence of SEQ ID NO: 60; a VH CDR1 having an amino acid sequence selected from SEQ ID NOs: 11 and 31; a VH FR2 having an amino acid sequence of SEQ ID NO: 61; and an amino acid sequence selected from SEQ ID NOs: 12 and 32 VH CDR2 having the amino acid sequence of SEQ ID NO: 62; VH CDR3 having an amino acid sequence selected from SEQ ID NOs: 13 and 33; and VH FR4 having the amino acid sequence of SEQ ID NO: 63
80. The isolated antibody or antigen-binding fragment thereof according to any of items 76 to 79, comprising an antibody VH region comprising
(Item 99)
VH FR1 having the amino acid sequence of SEQ ID NO: 60; VH CDR1 having the amino acid sequence of SEQ ID NO: 11; VH FR2 having the amino acid sequence of SEQ ID NO: 61; VH CDR2 having the amino acid sequence of SEQ ID NO: 12; VH FR3 having the amino acid sequence of SEQ ID NO: 13; and VH FR4 having the amino acid sequence of SEQ ID NO: 63
80. The isolated antibody or antigen-binding fragment thereof according to any of items 76 to 79, comprising an antibody VH region comprising
(Item 100)
VH FR1 having the amino acid sequence of SEQ ID NO: 60; VH CDR1 having the amino acid sequence of SEQ ID NO: 31; VH FR2 having the amino acid sequence of SEQ ID NO: 61; VH CDR2 having the amino acid sequence of SEQ ID NO: 32; VH FR3 having the amino acid sequence of SEQ ID NO: 33; and VH FR4 having the amino acid sequence of SEQ ID NO: 63
80. The isolated antibody or antigen-binding fragment thereof according to any of items 76 to 79, comprising an antibody VH region comprising
(Item 101)
A VH FR1 having an amino acid sequence of SEQ ID NO: 64; a VH CDR1 having an amino acid sequence selected from SEQ ID NOs: 11 and 31; a VH FR2 having an amino acid sequence of SEQ ID NO: 65; an amino acid sequence selected from SEQ ID NOs: 12 and 32 VH CDR2 having an amino acid sequence of SEQ ID NO: 66; VH CDR3 having an amino acid sequence selected from SEQ ID NOs: 13 and 33; and VH FR4 having an amino acid sequence of SEQ ID NO: 67
80. The isolated antibody or antigen-binding fragment thereof according to any of items 76 to 79, comprising an antibody VH region comprising
(Item 102)
VH FR1 having the amino acid sequence of SEQ ID NO: 64; VH CDR1 having the amino acid sequence of SEQ ID NO: 11; VH FR2 having the amino acid sequence of SEQ ID NO: 65; VH CDR2 having the amino acid sequence of SEQ ID NO: 12; VH FR3 having the amino acid sequence of SEQ ID NO: 13; and VH FR4 having the amino acid sequence of SEQ ID NO: 67
80. The isolated antibody or antigen-binding fragment thereof according to any of items 76 to 79, comprising an antibody VH region comprising
(Item 103)
VH FR1 having the amino acid sequence of SEQ ID NO: 64; VH CDR1 having the amino acid sequence of SEQ ID NO: 31; VH FR2 having the amino acid sequence of SEQ ID NO: 65; VH CDR2 having the amino acid sequence of SEQ ID NO: 32; VH FR3 having the amino acid sequence of SEQ ID NO: 33; and VH FR4 having the amino acid sequence of SEQ ID NO: 67
80. The isolated antibody or antigen-binding fragment thereof according to any of items 76 to 79, comprising an antibody VH region comprising
(Item 104)
VH FR1 having the amino acid sequence of SEQ ID NO: 64; VH CDR1 having an amino acid sequence selected from SEQ ID NO: 1 and 21; VH FR2 having the amino acid sequence of SEQ ID NO: 65; amino acid sequence selected from SEQ ID NO: 2 and 22 A VH CDR2 having an amino acid sequence of SEQ ID NO: 66; a VH CDR3 having an amino acid sequence selected from SEQ ID NOs: 3 and 23; and an antibody VH region comprising a VH FR4 having an amino acid sequence of SEQ ID NO: 67; VL FR1 having an amino acid sequence of No. 76; VL CDR1 having an amino acid sequence selected from SEQ ID Nos. 4 and 24; VL FR2 having an amino acid sequence of SEQ ID No. 77; having an amino acid sequence selected from SEQ ID Nos. 5 and 25 VL CDR2; SEQ ID NO: 78 Any of the preceding items comprising: VL FR3 having a mino acid sequence; VL CDR3 having an amino acid sequence selected from SEQ ID NOs: 6 and 26; and an antibody VL region comprising VL FR4 having an amino acid sequence of SEQ ID NO: 79 Or an antigen-binding fragment thereof.
(Item 105)
VH FR1 having the amino acid sequence of SEQ ID NO: 64; VH CDR1 having the amino acid sequence of SEQ ID NO: 1; VH FR2 having the amino acid sequence of SEQ ID NO: 65; VH CDR2 having the amino acid sequence of SEQ ID NO: 2; An antibody VH region comprising: VH CDR3 having the amino acid sequence of SEQ ID NO: 3; and VH FR4 having the amino acid sequence of SEQ ID NO: 67; VL FR1 having the amino acid sequence of SEQ ID NO: 76; VL CDR1 having the sequence: VL FR2 having the amino acid sequence of SEQ ID NO: 77; VL CDR2 having the amino acid sequence of SEQ ID NO: 5; VL FR3 having the amino acid sequence of SEQ ID NO: 78; VL CDR3 having the amino acid sequence of SEQ ID NO: 6; And the amino acid sequence of SEQ ID NO: 79 An isolated antibody or antigen-binding fragment thereof according to any of the preceding items, comprising an antibody VL region comprising VL FR4 having a sequence.
(Item 106)
VH FR1 having the amino acid sequence of SEQ ID NO: 64; VH CDR1 having the amino acid sequence of SEQ ID NO: 21; VH FR2 having the amino acid sequence of SEQ ID NO: 65; VH CDR2 having the amino acid sequence of SEQ ID NO: 22; An antibody VH region comprising: a VH CDR3 having the amino acid sequence of SEQ ID NO: 23; and a VH FR4 having an amino acid sequence of SEQ ID NO: 67; a VL FR1 having the amino acid sequence of SEQ ID NO: 76; an amino acid of SEQ ID NO: 24 VL CDR1 having the sequence: VL FR2 having the amino acid sequence of SEQ ID NO: 77; VL CDR2 having the amino acid sequence of SEQ ID NO: 25; VL FR3 having the amino acid sequence of SEQ ID NO: 78; VL CDR3 having the amino acid sequence of SEQ ID NO: 26; And SEQ ID NO: 79 An isolated antibody or an antigen-binding fragment thereof according to any one of the preceding items, comprising an antibody VL region comprising VL FR4 having the amino acid sequence of
(Item 107)
The isolated antibody or antigen-binding fragment thereof according to any of the preceding items, which is a chimeric antibody molecule, or an antigen-binding fragment thereof.
(Item 108)
108. The isolated antibody or antigen-binding fragment thereof according to item 107, comprising the variable region amino acid sequence of the antibody according to any of the preceding items and the human constant region amino acid sequence.
(Item 109)
An isolated antibody or antigen-binding fragment thereof according to any preceding item, which lacks complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC).
(Item 110)
Human LAG-3 protein (or human LAG-3Ig protein), for example, determined by Biacore analysis, 100 pM or less, 90 pM or less, 80 pM or less, 70 pM or less, 60 pM or less, 50 pM or less, 40 pM or less Of a dissociation constant of 30 pM or less or 25 pM or less (K _D The isolated antibody or antigen-binding fragment thereof according to any one of the preceding items, which binds with a).
(Item 111)
The isolated antibody or antigen-binding fragment thereof according to any one of the preceding items, which is an agonistic anti-LAG-3 antibody or an antigen-binding fragment thereof.
(Item 112)
The isolated antibody or antigen-binding fragment thereof according to any one of the preceding items, wherein the antibody or antigen-binding fragment thereof does not bind to the 30 amino acid extra loop sequence (SEQ ID NO: 40) of the first N-terminal D1 domain of human LAG-3 protein.
(Item 113)
A nucleic acid comprising a nucleotide sequence encoding the antibody or antigen-binding fragment thereof according to any of the preceding items.
(Item 114)
Comprising a nucleotide sequence of any of SEQ ID NO: 9, 10, 19, or 20 or a nucleotide sequence that is at least 80% identical to the nucleotide sequence of any of SEQ ID NO: 9, 10, 19, or 20 Nucleic acid.
(Item 115)
114. A recombinant vector comprising the nucleic acid according to item 113 or 114.
(Item 116)
114. A recombinant cell comprising the nucleic acid according to item 113 or 114, or the recombinant vector according to item 115.
(Item 117)
113. A pharmaceutical composition comprising the isolated antibody or antigen-binding fragment thereof according to any one of items 1-112 and a pharmaceutically acceptable carrier, excipient, or diluent.
(Item 118)
118. The isolated antibody or antigen-binding fragment thereof according to any one of items 1 to 112, or the pharmaceutical composition according to item 117, for use as a medicament.
(Item 119)
118. The isolated antibody or antigen-binding fragment thereof according to any one of items 1-112 or the pharmaceutical composition according to item 117 for use in the treatment of a T cell-mediated immune disorder.
(Item 120)
118. Use of the isolated antibody or antigen-binding fragment thereof according to any one of items 1 to 112 or the pharmaceutical composition according to item 117 in the manufacture of a medicament for treating a T cell-mediated immune disorder.
(Item 121)
118. A method of treating a T cell mediated immune disorder, comprising an effective amount of an isolated antibody or antigen-binding fragment thereof according to any one of items 1 to 112, or a pharmaceutical composition according to item 117. Administering to a subject in need of such treatment.
(Item 122)
121. The isolated antibody or antigen-binding fragment thereof according to item 119, the use according to item 120, or the method according to item 121, wherein the T-mediated immune disorder is an inflammatory disease or an autoimmune disorder.
(Item 123)
Said T cell-mediated immune disorder is an infection (of viruses, bacteria, fungi, and parasites), endotoxin shock associated with infection, sepsis, arthritis, rheumatoid arthritis, asthma, COPD, pelvic inflammatory disease, Alzheimer's disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, Peyronie's disease, celiac disease, gallbladder disease, hair follicle disease, peritonitis, psoriasis, vasculitis, surgical adhesions, stroke, type I diabetes, Lyme disease, Arthritis, meningoencephalitis, autoimmune uveitis; central and peripheral nervous system immune-mediated inflammatory disorders such as multiple sclerosis, lupus (such as systemic lupus erythematosus), and Guillain-Barre syndrome; atopic dermatitis , Autoimmune hepatitis, fibroalveolitis, Graves' disease, IgA nephropathy, idiopathic thrombocytopenic purpura, Meniere's disease, pemphigus, primary biliary cirrhosis, sarcoid Cis, scleroderma, Wegener's granulomatosis, other autoimmune disorders, pancreatitis, trauma (surgical trauma), graft-versus-host disease, graft rejection; including ischemic diseases such as myocardial infarction and atherosclerosis Item 119, selected from the group consisting of heart disease; intravascular coagulation, bone resorption, osteoporosis, osteoarthritis, periodontitis, and hypochlorhydia, or infertility associated with lack of maternal-tolerance 121. The isolated antibody or antigen-binding fragment thereof according to item 1, the use according to item 120, or the method according to item 121.

The light chain framework sequence of the humanized antibody (antibody IMP761) is:
VL FR1: DIVMTQTPSSLSASVGDRVTITC (SEQ ID NO: 76 );
VL FR2: WYQQRPGQAPKLLIY (SEQ ID NO: 77 );
VL FR3: GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (SEQ ID NO: 78 ); and VL FR4: FGQGTRLDIK (SEQ ID NO: 79 )
It is.

Claims (29)

Lymphocyte activation gene 3 binds to (LAG-3), the proliferation of CD4 ⁺ T cells and / or CD8 ⁺ T cells induced by antigen, and CD4 ⁺ induced / or antigen T cells and / or CD8 ⁺ An isolated antibody or antigen-binding fragment thereof that inhibits T cell activation ,
If necessary,
(I) the isolated antibody or antigen fragment thereof inhibits proliferation of antigen induced CD4 ⁺ T cells and antigen induced CD8 ⁺ T cells; and / or
(Ii) the isolated antibody or antigenic fragment thereof inhibits antigen-induced proliferation of CD8 ⁺ T cells more strongly than antigen-induced proliferation of CD4 ⁺ T cells; and / or
(Iii) the inhibition of proliferation of CD8 ⁺ T cells induced by antigen, a LAG-3 dependent and IL-2-independent,
Isolated antibody or antigen-binding fragment thereof . Binds to LAG-3 with greater affinity than monoclonal antibody 17B4 ; and / or
Inhibits binding of LAG-3 or IMP321 to MHC class II positive cells; and / or
Inhibits activation of antigen presenting cells (APC) induced by LAG-3, or monocyte activation induced by IMP321; and / or
2. The isolated antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof binds to an epitope of LAG-3 that overlaps with an MHC class II binding site of LAG-3 . One, two, or three complementarity determining regions (CDRs) of an antibody heavy chain variable (VH) region comprising the amino acid sequence of SEQ ID NO: 7, and / or an antibody light chain variable comprising the amino acid sequence of SEQ ID NO: 8 of (VL) region, one, two, or comprising three CDR, an isolated antibody or antigen binding fragment thereof according to 請 Motomeko 1 or 2,
If necessary,
(I) CDRs of the antibody VH region are selected from CDRs of amino acid sequences of SEQ ID NOs: 1, 2, 3, 21, 22, and 23, and CDRs of the antibody VL region are SEQ ID NOs: 4, 5, 6, Selected from CDRs of amino acid sequences 24, 25, and 26; and / or
(Ii) the isolated antibody or antigen-binding fragment thereof comprises an antibody VH region comprising VH CDR1, VH CDR2, and VH CDR3, wherein the VH CDR1 has an amino acid sequence selected from SEQ ID NOs: 1 and 21 And / or the VH CDR2 has an amino acid sequence selected from SEQ ID NOs: 2 and 22, and / or the VH CDR3 has an amino acid sequence selected from SEQ ID NOs: 3 and 23;
If necessary,
Whether the VH CDR1 has an amino acid sequence selected from SEQ ID NOs: 1 and 21, and the VH CDR2 has an amino acid sequence selected from SEQ ID NOs: 2 and 22;
Whether the VH CDR1 has an amino acid sequence selected from SEQ ID NOs: 1 and 21, and the VH CDR3 has an amino acid sequence selected from SEQ ID NOs: 3 and 23;
The VH CDR2 has an amino acid sequence selected from SEQ ID NOs: 2 and 22, and the VH CDR3 has an amino acid sequence selected from SEQ ID NOs: 3 and 23; or
The VH CDR1 has an amino acid sequence selected from SEQ ID NOs: 1 and 21, the VH CDR2 has an amino acid sequence selected from SEQ ID NOs: 2 and 22, and the VH CDR3 has SEQ ID NOs: 3 and 23 Having an amino acid sequence selected from: and / or
(Iii) the isolated antibody or antigen-binding fragment thereof comprises an antibody VL region comprising VL CDR1, VL CDR2, and VL CDR3, wherein the VL CDR1 has an amino acid sequence selected from SEQ ID NOs: 4 and 24 And / or the VL CDR2 has an amino acid sequence selected from SEQ ID NOs: 5 and 25 and / or the VL CDR3 has an amino acid sequence selected from SEQ ID NOs: 6 and 26;
If necessary,
Whether the VL CDR1 has an amino acid sequence selected from SEQ ID NOs: 4 and 24, and the VL CDR2 has an amino acid sequence selected from SEQ ID NOs: 5 and 25;
Whether the VL CDR1 has an amino acid sequence selected from SEQ ID NOs: 4 and 24, and the VL CDR3 has an amino acid sequence selected from SEQ ID NOs: 6 and 26;
The VL CDR2 has an amino acid sequence selected from SEQ ID NOs: 5 and 25, and the VL CDR3 has an amino acid sequence selected from SEQ ID NOs: 6 and 26; or
The VL CDR1 has an amino acid sequence selected from SEQ ID NOs: 4 and 24, the VL CDR2 has an amino acid sequence selected from SEQ ID NOs: 5 and 25, and the VL CDR3 has SEQ ID NOs: 6 and 26 Having an amino acid sequence selected from
An isolated antibody or antigen-binding fragment thereof. The VH CDR1 has an amino acid sequence selected from SEQ ID NOs: 1 and 21, the VH CDR2 has an amino acid sequence selected from SEQ ID NOs: 2 and 22, and the VH CDR3 has SEQ ID NOs: 3 and 23 And / or the VL CDR1 has an amino acid sequence selected from SEQ ID NOs: 4 and 24, and the VL CDR2 has an amino acid sequence selected from SEQ ID NOs: 5 and 25 The isolated antibody or antigen-binding fragment thereof according to (ii) or (iii) of claim 3 , wherein the VL CDR3 has an amino acid sequence selected from SEQ ID NOs: 6 and 26. The CDR of the antibody VH region is the CDR of the amino acid sequence of SEQ ID NO: 1, 2, and 3, and the CDR of the antibody VL region is the CDR of the amino acid sequence of SEQ ID NO: 4, 5, and 6 ; or
The CDR of the antibody VH region is the CDR of the amino acid sequence of SEQ ID NOs: 21, 22, and 23, and the CDR of the antibody VL region is the CDR of the amino acid sequence of SEQ ID NOs: 24, 25, and 26. 5. The isolated antibody or antigen-binding fragment thereof according to 3 or 4 . Comprising an antibody VH region having a CDR comprising the amino acid sequence of SEQ ID NO: 1, 2, and 3 and / or an antibody VL region having a CDR comprising the amino acid sequence of SEQ ID NO: 4, 5, and 6 ;
An antibody VH region having a CDR comprising the amino acid sequences of SEQ ID NOs: 21, 22, and 23, and / or an antibody VL region having a CDR comprising the amino acid sequences of SEQ ID NOs: 24, 25, and 26,
The isolated antibody or antigen-binding fragment thereof according to any one of claims 1 to 5 . (A) SEQ ID NO: 1, or VH CDR1 region comprising 1, 2, 3, 4, or 5 amino acid substitutions, deletions or additions compared to SEQ ID NO: 1; (b) SEQ ID NO: 2 or a VH CDR2 region comprising 1, 2, 3, 4, or 5 amino acid substitutions, deletions or additions compared to SEQ ID NO: 2; and (c) SEQ ID NO: 3, or a heavy chain variable region comprising a VH CDR3 region comprising 1, 2, 3, 4, or 5 amino acid substitutions, deletions or additions compared to SEQ ID NO: 3; and / or Or (a) VL CDR1 region comprising SEQ ID NO: 4 or 1, 2, 3, 4, or 5 amino acid substitutions, deletions or additions compared to SEQ ID NO: 4 (B) SEQ ID NO: 5, or a VL CDR2 region comprising 1, 2, 3, 4, or 5 amino acid substitutions, deletions or additions compared to SEQ ID NO: 5; and ( c) Light chain variable comprising a VL CDR3 region comprising SEQ ID NO: 6, or an amino acid sequence having 1, 2, 3, 4, or 5 amino acid substitutions, deletions or additions compared to SEQ ID NO: 6. Including territory ; or
(A) SEQ ID NO: 21, or a VH CDR1 region comprising 1, 2, 3, 4, or 5 amino acid substitutions, deletions or additions compared to SEQ ID NO: 21; (b) SEQ ID NO: 22 or a VH CDR2 region comprising 1, 2, 3, 4, or 5 amino acid substitutions, deletions or additions compared to SEQ ID NO: 22; and (c) SEQ ID NO: 23, or a heavy chain variable region comprising a VH CDR3 region comprising 1, 2, 3, 4, or 5 amino acid substitutions, deletions or additions compared to SEQ ID NO: 23; and / or Or (a) SEQ ID NO: 24 or an amino acid sequence having 1, 2, 3, 4, or 5 amino acid substitutions, deletions or additions compared to SEQ ID NO: 24 L CDR1 region; (b) VL CDR2 region comprising amino acid sequence having 1, 2, 3, 4, or 5 amino acid substitutions, deletions or additions compared to SEQ ID NO: 25 or SEQ ID NO: 25 And (c) comprising SEQ ID NO: 26 or a VL CDR3 region comprising 1, 2, 3, 4, or 5 amino acid substitutions, deletions or additions compared to SEQ ID NO: 26 The isolated antibody or antigen-binding fragment thereof according to any one of claims 1 to 6 , comprising a light chain variable region . An antibody VH region comprising the amino acid sequence of SEQ ID NO: 7, or an amino acid sequence that is at least 60% identical to the amino acid sequence of SEQ ID NO: 7, and / or the amino acid sequence of SEQ ID NO: 8, or the amino acid sequence of SEQ ID NO: 8, at least 60% comprising an antibody VL region comprising an amino acid sequence identical, an isolated antibody or antigen binding fragment thereof according to any one of the 請 Motomeko 1 7,
If necessary,
Antibody VH comprising an amino acid sequence that is at least 60% identical to the amino acid sequence of SEQ ID NO: 7
A region and an antibody VL region comprising an amino acid sequence that is at least 60% identical to the amino acid sequence of SEQ ID NO: 8;
An antibody VH region comprising an amino acid sequence that is at least 60% identical to the amino acid sequence of SEQ ID NO: 7, and an antibody VL region comprising the amino acid sequence of SEQ ID NO: 8;
An antibody VH region comprising the amino acid sequence of SEQ ID NO: 7 and an antibody VL region comprising an amino acid sequence that is at least 60% identical to the amino acid sequence of SEQ ID NO: 8; or
An isolated antibody or antigen-binding fragment thereof, comprising an antibody VH region comprising the amino acid sequence of SEQ ID NO: 7 and an antibody VL region comprising the amino acid sequence of SEQ ID NO: 8 . One, two or three CDRs of the antibody VH region comprising the amino acid sequence of SEQ ID NO: 17 and / or one, two or three CDRs of the antibody VL region comprising the amino acid sequence of SEQ ID NO: 18 the containing an isolated antibody or antigen binding fragment thereof according to any one of the 請 Motomeko 1 8,
If necessary,
(I) CDRs of the antibody VH region are selected from CDRs of amino acid sequences of SEQ ID NOs: 11, 12, 13, 31, 32, and 33, and CDRs of the antibody VL region are SEQ ID NOs: 14, 15, 16, Selected from CDRs of amino acid sequences 34, 35, and 36; and / or
(Ii) the isolated antibody or antigen-binding fragment thereof comprises an antibody VH region comprising VH CDR1, VH CDR2, and VH CDR3, wherein the VH CDR1 has an amino acid sequence selected from SEQ ID NOs: 11 and 31 And / or the VH CDR2 has an amino acid sequence selected from SEQ ID NOs: 12 and 32 and / or the VH CDR3 has an amino acid sequence selected from SEQ ID NOs: 13 and 33;
If necessary,
Whether the VH CDR1 has an amino acid sequence selected from SEQ ID NOs: 11 and 31, and the VH CDR2 has an amino acid sequence selected from SEQ ID NOs: 12 and 32;
Whether the VH CDR1 has an amino acid sequence selected from SEQ ID NOs: 11 and 31, and the VH CDR3 has an amino acid sequence selected from SEQ ID NOs: 13 and 33;
The VH CDR2 has an amino acid sequence selected from SEQ ID NOs: 12 and 32, and the VH CDR3 has an amino acid sequence selected from SEQ ID NOs: 13 and 33; or
The VH CDR1 has an amino acid sequence selected from SEQ ID NOs: 11 and 31, the VH CDR2 has an amino acid sequence selected from SEQ ID NOs: 12 and 32, and the VH CDR3 has SEQ ID NOs: 13 and 33 And / or having an amino acid sequence selected from
(Iii) the isolated antibody or antigen-binding fragment thereof comprises an antibody VL region comprising VL CDR1, VL CDR2, and VL CDR3, wherein the VL CDR1 has an amino acid sequence selected from SEQ ID NOs: 14 and 34 And / or the VL CDR2 has an amino acid sequence selected from SEQ ID NOs: 15 and 35 and / or the VL CDR3 has an amino acid sequence selected from SEQ ID NOs: 16 and 36;
If necessary,
Whether the VL CDR1 has an amino acid sequence selected from SEQ ID NOs: 14 and 34, and the VL CDR2 has an amino acid sequence selected from SEQ ID NOs: 15 and 35;
Whether the VL CDR1 has an amino acid sequence selected from SEQ ID NOs: 14 and 34, and the VL CDR3 has an amino acid sequence selected from SEQ ID NOs: 16 and 36;
The VL CDR2 has an amino acid sequence selected from SEQ ID NOs: 15 and 35, and the VL CDR3 has an amino acid sequence selected from SEQ ID NOs: 16 and 36; or
The VL CDR1 has an amino acid sequence selected from SEQ ID NOs: 14 and 34, the VL CDR2 has an amino acid sequence selected from SEQ ID NOs: 15 and 35, and the VL CDR3 has SEQ ID NOs: 16 and 36 Having an amino acid sequence selected from
Isolated antibody or antigen-binding fragment thereof . The VH CDR1 has an amino acid sequence selected from SEQ ID NOs: 11 and 31, the VH CDR2 has an amino acid sequence selected from SEQ ID NOs: 12 and 32, and the VH CDR3 has SEQ ID NOs: 13 and 33. And / or the VL CDR1 has an amino acid sequence selected from SEQ ID NOs: 14 and 34, and the VL CDR2 has an amino acid sequence selected from SEQ ID NOs: 15 and 35 The isolated antibody or antigen-binding fragment thereof according to (ii) or (iii) of claim 9 , wherein the VL CDR3 has an amino acid sequence selected from SEQ ID NOs: 16 and 36. The CDR of the antibody VH region is the CDR of the amino acid sequence of SEQ ID NOs: 11, 12, and 13, and the CDR of the antibody VL region is the CDR of the amino acid sequence of SEQ ID NOs: 14, 15, and 16 ; or
The CDR of the antibody VH region is a CDR of the amino acid sequence of SEQ ID NOs: 31, 32, and 33, and the CDR of the antibody VL region is a CDR of the amino acid sequence of SEQ ID NOs: 34, 35, and 36. The isolated antibody or antigen-binding fragment thereof according to 9 or 10 . An antibody VH region having a CDR comprising the amino acid sequences of SEQ ID NOs: 11, 12, and 13 and / or an antibody VL region having a CDR comprising the amino acid sequences of SEQ ID NOs: 14, 15, and 16 ; or
An antibody VH region having a CDR comprising the amino acid sequences of SEQ ID NOs: 31, 32, and 33 and / or an antibody VL region having a CDR comprising the amino acid sequences of SEQ ID NOs: 34, 35, and 36
The isolated antibody or antigen-binding fragment thereof according to any one of claims 1 to 11 , which comprises (A) SEQ ID NO: 11 or a VH CDR1 region comprising 1, 2, 3, 4, or 5 amino acid substitutions, deletions or additions compared to SEQ ID NO: 11; (b) SEQ ID NO: 12, or a VH CDR2 region comprising 1, 2, 3, 4, or 5 amino acid substitutions, deletions or additions compared to SEQ ID NO: 12; and (c) SEQ ID NO: 13, or a CDR comprising an amino acid sequence having 1, 2, 3, 4, or 5 amino acid substitutions, deletions or additions compared to SEQ ID NO: 13
A heavy chain variable region comprising three regions; and / or (a) SEQ ID NO: 14, or 1, 2, 3, 4, or 5 amino acid substitutions, deletions or additions compared to SEQ ID NO: 14. A VL CDR1 region comprising an amino acid sequence having; (b) an amino acid sequence having 1, 2, 3, 4, or 5 amino acid substitutions, deletions or additions compared to SEQ ID NO: 15 or SEQ ID NO: 15; A VL CDR2 region comprising; and (c) comprising SEQ ID NO: 16, or an amino acid sequence having 1, 2, 3, 4, or 5 amino acid substitutions, deletions or additions compared to SEQ ID NO: 16 A light chain variable region comprising a VL CDR3 region ; or
(A) SEQ ID NO: 31 or a VH CDR1 region comprising 1, 2, 3, 4, or 5 amino acid substitutions, deletions or additions compared to SEQ ID NO: 31; (b) SEQ ID NO: 32, or a VH CDR2 region comprising 1, 2, 3, 4, or 5 amino acid substitutions, deletions or additions compared to SEQ ID NO: 32; and (c) SEQ ID NO: 33, or a heavy chain variable region comprising a CDR3 region comprising an amino acid sequence having 1, 2, 3, 4, or 5 amino acid substitutions, deletions or additions compared to SEQ ID NO: 33; and / or (A) VL comprising SEQ ID NO: 34 or an amino acid sequence having 1, 2, 3, 4, or 5 amino acid substitutions, deletions or additions compared to SEQ ID NO: 34 DR1 region; (b) VL CDR2 region comprising amino acid sequence having 1, 2, 3, 4, or 5 amino acid substitutions, deletions or additions compared to SEQ ID NO: 35 or SEQ ID NO: 35; And (c) SEQ ID NO: 36, or a lighter comprising a VL CDR3 region comprising 1, 2, 3, 4, or 5 amino acid substitutions, deletions or additions compared to SEQ ID NO: 36. Including the chain variable region,
The isolated antibody or antigen-binding fragment thereof according to any one of claims 1 to 12 . An antibody VH region comprising the amino acid sequence of SEQ ID NO: 17, or an amino acid sequence that is at least 60% identical to the amino acid sequence of SEQ ID NO: 17, and / or the amino acid sequence of SEQ ID NO: 18, or at least 60% with the amino acid sequence of SEQ ID NO: 18 comprising an antibody VL region comprising an amino acid sequence identical, an isolated antibody or antigen binding fragment thereof according to any one of the 請 Motomeko 1 13,
If necessary,
An antibody VH region comprising an amino acid sequence at least 60% identical to the amino acid sequence of SEQ ID NO: 17, and an antibody VL region comprising an amino acid sequence at least 60% identical to the amino acid sequence of SEQ ID NO: 18;
An antibody VH region comprising an amino acid sequence at least 60% identical to the amino acid sequence of SEQ ID NO: 17 and an antibody VL region comprising the amino acid sequence of SEQ ID NO: 18;
An antibody VH region comprising the amino acid sequence of SEQ ID NO: 17 and an antibody VL region comprising an amino acid sequence at least 60% identical to the amino acid sequence of SEQ ID NO: 18; or
An antibody VH region comprising the amino acid sequence of SEQ ID NO: 17 and an antibody VL region comprising the amino acid sequence of SEQ ID NO: 18
An isolated antibody or antigen-binding fragment thereof, comprising The isolated antibody or antigen-binding fragment thereof according to any one of claims 1 to 14 , comprising a monoclonal antibody or an antigen-binding fragment thereof , or a humanized monoclonal antibody or an antigen-binding fragment thereof. Comprising a humanized light chain framework regions, an isolated antibody or antigen binding fragment thereof according to any one of 請 Motomeko 1 to 15,
If necessary,
(I) the humanized light chain framework region comprises an amino acid sequence having any of the amino acid substitutions shown in Table 27 for VL ₁ , VL ₂ , VL ₃ , or VL ₄ ; and / or
(Ii) the humanized light chain framework region comprises an amino acid sequence of any of SEQ ID NOs: 68-83; optionally, the isolated antibody or antigen-binding fragment thereof is
VL framework region 1 of SEQ ID NO: 68 (VL FR1); VL FR2 of SEQ ID NO: 69; VL FR3 of SEQ ID NO: 70; and VL FR4 of SEQ ID NO: 71;
VL framework region 1 of SEQ ID NO: 72 (VL FR1); VL FR2 of SEQ ID NO: 73; VL FR3 of SEQ ID NO: 74; and VL FR4 of SEQ ID NO: 75;
VL framework region 1 of SEQ ID NO: 76 (VL FR1); VL FR2 of SEQ ID NO: 77; VL FR3 of SEQ ID NO: 78; and VL FR4 of SEQ ID NO: 79; or
VL framework region 1 of SEQ ID NO: 80 (VL FR1); VL FR2 of SEQ ID NO: 81; VL FR3 of SEQ ID NO: 82; and VL FR4 of SEQ ID NO: 83
And / or
(Iii) the isolated antibody or antigen-binding fragment thereof,
VL FR1 having an amino acid sequence of SEQ ID NO: 68; VL CDR1 having an amino acid sequence selected from SEQ ID NOs: 4 and 24; VL FR2 having an amino acid sequence of SEQ ID NO: 69; and an amino acid sequence selected from SEQ ID NOs: 5 and 25 A VL CDR2 having an amino acid sequence of SEQ ID NO: 70; a VL CDR3 having an amino acid sequence selected from SEQ ID NOs: 6 and 26; and a VL FR4 having an amino acid sequence of SEQ ID NO: 71;
VL FR1 having the amino acid sequence of SEQ ID NO: 68; VL CDR1 having the amino acid sequence of SEQ ID NO: 4; VL FR2 having the amino acid sequence of SEQ ID NO: 69; VL CDR2 having the amino acid sequence of SEQ ID NO: 5; VL FR3 having the amino acid sequence of SEQ ID NO: 6; and VL FR4 having the amino acid sequence of SEQ ID NO: 71;
VL FR1 having the amino acid sequence of SEQ ID NO: 68; VL CDR1 having the amino acid sequence of SEQ ID NO: 24; VL FR2 having the amino acid sequence of SEQ ID NO: 69; VL CDR2 having the amino acid sequence of SEQ ID NO: 25; VL FR3 having the amino acid sequence of SEQ ID NO: 26; and VL FR4 having the amino acid sequence of SEQ ID NO: 71;
VL FR1 having an amino acid sequence of SEQ ID NO: 72; VL CDR1 having an amino acid sequence selected from SEQ ID NOs: 4 and 24; VL FR2 having an amino acid sequence of SEQ ID NO: 73; and an amino acid sequence selected from SEQ ID NOs: 5 and 25 A VL CDR2 having an amino acid sequence of SEQ ID NO: 74; a VL CDR3 having an amino acid sequence selected from SEQ ID NOs: 6 and 26; and a VL FR4 having an amino acid sequence of SEQ ID NO: 75;
VL FR1 having the amino acid sequence of SEQ ID NO: 72; VL CDR1 having the amino acid sequence of SEQ ID NO: 4; VL FR2 having the amino acid sequence of SEQ ID NO: 73; VL CDR2 having the amino acid sequence of SEQ ID NO: 5; A VL FR3 having the amino acid sequence of SEQ ID NO: 6; and a VL FR4 having the amino acid sequence of SEQ ID NO: 75;
VL FR1 having the amino acid sequence of SEQ ID NO: 72; VL CDR1 having the amino acid sequence of SEQ ID NO: 24; VL FR2 having the amino acid sequence of SEQ ID NO: 73; VL CDR2 having the amino acid sequence of SEQ ID NO: 25; A VL CDR3 having the amino acid sequence of SEQ ID NO: 26; and a VL FR4 having the amino acid sequence of SEQ ID NO: 75;
VL FR1 having an amino acid sequence of SEQ ID NO: 76; VL CDR1 having an amino acid sequence selected from SEQ ID NOs: 4 and 24; VL FR2 having an amino acid sequence of SEQ ID NO: 77; and an amino acid sequence selected from SEQ ID NOs: 5 and 25 A VL CDR2 having an amino acid sequence of SEQ ID NO: 78; a VL CDR3 having an amino acid sequence selected from SEQ ID NOs: 6 and 26; and a VL FR4 having an amino acid sequence of SEQ ID NO: 79;
VL FR1 having the amino acid sequence of SEQ ID NO: 76; VL CDR1 having the amino acid sequence of SEQ ID NO: 4; VL FR2 having the amino acid sequence of SEQ ID NO: 77; VL CDR2 having the amino acid sequence of SEQ ID NO: 5; VL FR3 having the amino acid sequence of SEQ ID NO: 6; and VL FR4 having the amino acid sequence of SEQ ID NO: 79;
VL FR1 having the amino acid sequence of SEQ ID NO: 76; VL CDR1 having the amino acid sequence of SEQ ID NO: 24; VL FR2 having the amino acid sequence of SEQ ID NO: 77; VL CDR2 having the amino acid sequence of SEQ ID NO: 25; VL FR3 having the amino acid sequence of SEQ ID NO: 26; and VL FR4 having the amino acid sequence of SEQ ID NO: 79;
VL FR1 having an amino acid sequence of SEQ ID NO: 80; VL CDR1 having an amino acid sequence selected from SEQ ID NOs: 4 and 24; VL FR2 having an amino acid sequence of SEQ ID NO: 81; and an amino acid sequence selected from SEQ ID NOs: 5 and 25 A VL CDR2 having an amino acid sequence of SEQ ID NO: 82; a VL CDR3 having an amino acid sequence selected from SEQ ID NOs: 6 and 26; and a VL FR4 having an amino acid sequence of SEQ ID NO: 83;
VL FR1 having the amino acid sequence of SEQ ID NO: 80; VL CDR1 having the amino acid sequence of SEQ ID NO: 4; VL FR2 having the amino acid sequence of SEQ ID NO: 81; VL CDR2 having the amino acid sequence of SEQ ID NO: 5; A VL CDR3 having an amino acid sequence selected from SEQ ID NO: 6; and a VL FR4 having an amino acid sequence of SEQ ID NO: 83; or
VL FR1 having the amino acid sequence of SEQ ID NO: 80; VL CDR1 having the amino acid sequence of SEQ ID NO: 24; VL FR2 having the amino acid sequence of SEQ ID NO: 81; VL CDR2 having the amino acid sequence selected from SEQ ID NO: 25; SEQ ID NO: 82 VL FR3 having an amino acid sequence of: VL CDR3 having an amino acid sequence selected from SEQ ID NO: 26; and VL FR4 having an amino acid sequence of SEQ ID NO: 83
An antibody VL region comprising; and / or
(Iv) the isolated antibody or antigen-binding fragment thereof,
VL FR1 having an amino acid sequence of SEQ ID NO: 68; VL CDR1 having an amino acid sequence selected from SEQ ID NOs: 14 and 34; VL FR2 having an amino acid sequence of SEQ ID NO: 69; and an amino acid sequence selected from SEQ ID NOs: 15 and 35 A VL CDR2 having an amino acid sequence of SEQ ID NO: 70; a VL CDR3 having an amino acid sequence selected from SEQ ID NOs: 16 and 36; and a VL FR4 having an amino acid sequence of SEQ ID NO: 71;
VL FR1 having the amino acid sequence of SEQ ID NO: 68; VL CDR1 having the amino acid sequence of SEQ ID NO: 14; VL FR2 having the amino acid sequence of SEQ ID NO: 69; VL CDR2 having the amino acid sequence of SEQ ID NO: 15; VL FR3 having the amino acid sequence of SEQ ID NO: 16; and VL FR4 having the amino acid sequence of SEQ ID NO: 71;
VL FR1 having the amino acid sequence of SEQ ID NO: 68; VL CDR1 having the amino acid sequence of SEQ ID NO: 34; VL FR2 having the amino acid sequence of SEQ ID NO: 69; VL CDR2 having the amino acid sequence of SEQ ID NO: 35; VL FR3 having the amino acid sequence of SEQ ID NO: 36; and VL FR4 having the amino acid sequence of SEQ ID NO: 71;
VL FR1 having an amino acid sequence of SEQ ID NO: 72; VL CDR1 having an amino acid sequence selected from SEQ ID NOs: 14 and 34; VL FR2 having an amino acid sequence of SEQ ID NO: 73; and an amino acid sequence selected from SEQ ID NOs: 15 and 35 A VL CDR2 having an amino acid sequence of SEQ ID NO: 74; a VL CDR3 having an amino acid sequence selected from SEQ ID NOs: 16 and 36; and a VL FR4 having an amino acid sequence of SEQ ID NO: 75;
VL FR1 having the amino acid sequence of SEQ ID NO: 72; VL CDR1 having the amino acid sequence of SEQ ID NO: 14; VL FR2 having the amino acid sequence of SEQ ID NO: 73; VL CDR2 having the amino acid sequence of SEQ ID NO: 15; VL FR3 having the amino acid sequence of SEQ ID NO: 16; and VL FR4 having the amino acid sequence of SEQ ID NO: 75;
VL FR1 having the amino acid sequence of SEQ ID NO: 72; VL CDR1 having the amino acid sequence of SEQ ID NO: 34; VL FR2 having the amino acid sequence of SEQ ID NO: 73; VL CDR2 having the amino acid sequence of SEQ ID NO: 35; VL FR3 having the amino acid sequence of SEQ ID NO: 36; and VL FR4 having the amino acid sequence of SEQ ID NO: 75;
VL FR1 having an amino acid sequence of SEQ ID NO: 76; VL CDR1 having an amino acid sequence selected from SEQ ID NOs: 14 and 34; VL FR2 having an amino acid sequence of SEQ ID NO: 77; and an amino acid sequence selected from SEQ ID NOs: 15 and 35 A VL CDR2 having an amino acid sequence of SEQ ID NO: 78; a VL CDR3 having an amino acid sequence selected from SEQ ID NOs: 16 and 36; and a VL FR4 having an amino acid sequence of SEQ ID NO: 79;
VL FR1 having the amino acid sequence of SEQ ID NO: 76; VL CDR1 having the amino acid sequence of SEQ ID NO: 14; VL FR2 having the amino acid sequence of SEQ ID NO: 77; VL CDR2 having the amino acid sequence of SEQ ID NO: 15; VL FR3 having the amino acid sequence of SEQ ID NO: 16; and VL FR4 having the amino acid sequence of SEQ ID NO: 79;
VL FR1 having the amino acid sequence of SEQ ID NO: 76; VL CDR1 having the amino acid sequence of SEQ ID NO: 34; VL FR2 having the amino acid sequence of SEQ ID NO: 77; VL CDR2 having the amino acid sequence of SEQ ID NO: 35; VL FR3 having the amino acid sequence of SEQ ID NO: 36; and VL FR4 having the amino acid sequence of SEQ ID NO: 79;
VL FR1 having an amino acid sequence of SEQ ID NO: 80; VL CDR1 having an amino acid sequence selected from SEQ ID NOs: 14 and 34; VL FR2 having an amino acid sequence of SEQ ID NO: 81; and an amino acid sequence selected from SEQ ID NOs: 15 and 35 A VL CDR2 having an amino acid sequence of SEQ ID NO: 82; a VL CDR3 having an amino acid sequence selected from SEQ ID NOs: 16 and 36; and a VL FR4 having an amino acid sequence of SEQ ID NO: 83;
VL FR1 having the amino acid sequence of SEQ ID NO: 80; VL CDR1 having the amino acid sequence of SEQ ID NO: 14; VL FR2 having the amino acid sequence of SEQ ID NO: 81; VL CDR2 having the amino acid sequence of SEQ ID NO: 15; VL FR3 having the amino acid sequence of SEQ ID NO: 16; and VL FR4 having the amino acid sequence of SEQ ID NO: 83; or
VL FR1 having the amino acid sequence of SEQ ID NO: 80; VL CDR1 having the amino acid sequence of SEQ ID NO: 34; VL FR2 having the amino acid sequence of SEQ ID NO: 81; VL CDR2 having the amino acid sequence of SEQ ID NO: 35; VL FR3 having the amino acid sequence of SEQ ID NO: 36; and VL FR4 having the amino acid sequence of SEQ ID NO: 83
An isolated antibody or antigen-binding fragment thereof comprising an antibody VL region comprising It comprises a humanized heavy chain framework regions, an isolated antibody or antigen binding fragment thereof according to any one of the 請 Motomeko 1 16,
If necessary,
(I) the humanized heavy chain framework region comprises an amino acid sequence having any of the amino acid substitutions shown in Table 26 for VH ₁ , VH ₂ , VH ₃ , or VH ₄ ; and / or
(Ii) the humanized heavy chain framework region comprises an amino acid sequence of any of SEQ ID NOs: 52-67;
Optionally, the isolated antibody or antigen-binding fragment thereof is
VH framework region 1 of SEQ ID NO: 52 (VH FR1); VH FR2 of SEQ ID NO: 53; VH FR3 of SEQ ID NO: 54; and VH FR4 of SEQ ID NO: 55;
VH framework region 1 of SEQ ID NO: 56 (VH FR1); VH FR2 of SEQ ID NO: 57; VH FR3 of SEQ ID NO: 58; and VH FR4 of SEQ ID NO: 59;
VH framework region 1 of SEQ ID NO: 60 (VH FR1); VH FR2 of SEQ ID NO: 61; VH FR3 of SEQ ID NO: 62; and VH FR4 of SEQ ID NO: 63; or
VH framework region 1 of SEQ ID NO: 64 (VH FR1); VH FR2 of SEQ ID NO: 65; VH FR3 of SEQ ID NO: 66; and VH FR4 of SEQ ID NO: 67
And / or
(Iii) the isolated antibody or antigen-binding fragment thereof,
VH FR1 having an amino acid sequence of SEQ ID NO: 52; VH CDR1 having an amino acid sequence selected from SEQ ID NOs: 1 and 21; VH FR2 having an amino acid sequence of SEQ ID NO: 53; amino acid sequences selected from SEQ ID NOs: 2 and 22 VH CDR2 having the amino acid sequence of SEQ ID NO: 54; VH CDR3 having an amino acid sequence selected from SEQ ID NOs: 3 and 23; and VH FR4 having the amino acid sequence of SEQ ID NO: 55;
VH FR1 having the amino acid sequence of SEQ ID NO: 52; VH CDR1 having the amino acid sequence of SEQ ID NO: 1; VH FR2 having the amino acid sequence of SEQ ID NO: 53; VH CDR2 having the amino acid sequence of SEQ ID NO: 2; VH FR3 having the amino acid sequence of SEQ ID NO: 3; and VH FR4 having the amino acid sequence of SEQ ID NO: 55;
VH FR1 having the amino acid sequence of SEQ ID NO: 52; VH CDR1 having the amino acid sequence of SEQ ID NO: 21; VH FR2 having the amino acid sequence of SEQ ID NO: 53; VH CDR2 having the amino acid sequence of SEQ ID NO: 22; VH FR3 having the amino acid sequence of SEQ ID NO: 23; and VH FR4 having the amino acid sequence of SEQ ID NO: 55;
VH FR1 having an amino acid sequence of SEQ ID NO: 56; VH CDR1 having an amino acid sequence selected from SEQ ID NOs: 1 and 21; VH FR2 having an amino acid sequence of SEQ ID NO: 57; and an amino acid sequence selected from SEQ ID NOs: 2 and 22 VH CDR2 having the amino acid sequence of SEQ ID NO: 58; VH CDR3 having an amino acid sequence selected from SEQ ID NOs: 3 and 23; and VH FR4 having the amino acid sequence of SEQ ID NO: 59;
VH FR1 having the amino acid sequence of SEQ ID NO: 56; VH CDR1 having the amino acid sequence of SEQ ID NO: 1; VH FR2 having the amino acid sequence of SEQ ID NO: 57; VH CDR2 having the amino acid sequence of SEQ ID NO: 2; VH FR3 having the amino acid sequence of SEQ ID NO: 3; and VH FR4 having the amino acid sequence of SEQ ID NO: 59;
VH FR1 having the amino acid sequence of SEQ ID NO: 56; VH CDR1 having the amino acid sequence of SEQ ID NO: 21; VH FR2 having the amino acid sequence of SEQ ID NO: 57; VH CDR2 having the amino acid sequence of SEQ ID NO: 22; VH FR3 having the amino acid sequence of SEQ ID NO: 23; and VH FR4 having the amino acid sequence of SEQ ID NO: 59;
A VH FR1 having the amino acid sequence of SEQ ID NO: 60; a VH CDR1 having an amino acid sequence selected from SEQ ID NOs: 1 and 21; a VH FR2 having an amino acid sequence of SEQ ID NO: 61; and an amino acid sequence selected from SEQ ID NOs: 2 and 22 A VH CDR2 having an amino acid sequence of SEQ ID NO: 62; a VH CDR3 having an amino acid sequence selected from SEQ ID NOs: 3 and 23; and a VH FR4 having an amino acid sequence of SEQ ID NO: 63;
VH FR1 having the amino acid sequence of SEQ ID NO: 60; VH CDR1 having the amino acid sequence of SEQ ID NO: 1; VH FR2 having the amino acid sequence of SEQ ID NO: 61; VH CDR2 having the amino acid sequence of SEQ ID NO: 2; VH FR3 having the amino acid sequence of SEQ ID NO: 3; and VH FR4 having the amino acid sequence of SEQ ID NO: 63;
VH FR1 having the amino acid sequence of SEQ ID NO: 60; VH CDR1 having the amino acid sequence of SEQ ID NO: 21; VH FR2 having the amino acid sequence of SEQ ID NO: 61; VH CDR2 having the amino acid sequence of SEQ ID NO: 22; VH FR3 having the amino acid sequence of SEQ ID NO: 23; and VH FR4 having the amino acid sequence of SEQ ID NO: 63;
VH FR1 having the amino acid sequence of SEQ ID NO: 64; VH CDR1 having an amino acid sequence selected from SEQ ID NO: 1 and 21; VH FR2 having the amino acid sequence of SEQ ID NO: 65; amino acid sequence selected from SEQ ID NO: 2 and 22 A VH CDR2 having an amino acid sequence of SEQ ID NO: 66; a VH CDR3 having an amino acid sequence selected from SEQ ID NOs: 3 and 23; and a VH FR4 having an amino acid sequence of SEQ ID NO: 67;
VH FR1 having the amino acid sequence of SEQ ID NO: 64; VH CDR1 having the amino acid sequence of SEQ ID NO: 1; VH FR2 having the amino acid sequence of SEQ ID NO: 65; VH CDR2 having the amino acid sequence of SEQ ID NO: 2; VH FR3 having the amino acid sequence of SEQ ID NO: 3; and VH FR4 having the amino acid sequence of SEQ ID NO: 67; or
VH FR1 having the amino acid sequence of SEQ ID NO: 64; VH CDR1 having the amino acid sequence of SEQ ID NO: 21; VH FR2 having the amino acid sequence of SEQ ID NO: 65; VH CDR2 having the amino acid sequence of SEQ ID NO: 22; VH FR3 having the amino acid sequence of SEQ ID NO: 23; and VH FR4 having the amino acid sequence of SEQ ID NO: 67
An antibody VH region comprising; and / or
(Iv) the isolated antibody or antigen-binding fragment thereof,
A VH FR1 having an amino acid sequence of SEQ ID NO: 52; a VH CDR1 having an amino acid sequence selected from SEQ ID NOs: 11 and 31; a VH FR2 having an amino acid sequence of SEQ ID NO: 53; and an amino acid sequence selected from SEQ ID NOs: 12 and 32 VH CDR2 having the amino acid sequence of SEQ ID NO: 54; VH CDR3 having an amino acid sequence selected from SEQ ID NOs: 3 and 33; and VH FR4 having the amino acid sequence of SEQ ID NO: 55;
VH FR1 having the amino acid sequence of SEQ ID NO: 52; VH CDR1 having the amino acid sequence of SEQ ID NO: 11; VH FR2 having the amino acid sequence of SEQ ID NO: 53; VH CDR2 having the amino acid sequence of SEQ ID NO: 12; VH FR3 having the amino acid sequence of SEQ ID NO: 3; and VH FR4 having the amino acid sequence of SEQ ID NO: 55;
VH FR1 having the amino acid sequence of SEQ ID NO: 52; VH CDR1 having the amino acid sequence of SEQ ID NO: 31; VH FR2 having the amino acid sequence of SEQ ID NO: 53; VH CDR2 having the amino acid sequence of SEQ ID NO: 32; VH FR3 having the amino acid sequence of SEQ ID NO: 33; and VH FR4 having the amino acid sequence of SEQ ID NO: 55;
VH FR1 having an amino acid sequence of SEQ ID NO: 56; VH CDR1 having an amino acid sequence selected from SEQ ID NOs: 11 and 31; VH FR2 having an amino acid sequence of SEQ ID NO: 57; and an amino acid sequence selected from SEQ ID NOs: 12 and 32 VH CDR2 having the amino acid sequence of SEQ ID NO: 58; VH CDR3 having an amino acid sequence selected from SEQ ID NOs: 13 and 33; and VH FR4 having the amino acid sequence of SEQ ID NO: 59;
VH FR1 having the amino acid sequence of SEQ ID NO: 56; VH CDR1 having the amino acid sequence of SEQ ID NO: 11; VH FR2 having the amino acid sequence of SEQ ID NO: 57; VH CDR2 having the amino acid sequence of SEQ ID NO: 12; VH FR3 having the amino acid sequence of SEQ ID NO: 13; and VH FR4 having the amino acid sequence of SEQ ID NO: 59;
VH FR1 having the amino acid sequence of SEQ ID NO: 56; VH CDR1 having the amino acid sequence of SEQ ID NO: 31; VH FR2 having the amino acid sequence of SEQ ID NO: 57; VH CDR2 having the amino acid sequence of SEQ ID NO: 32; VH FR3 having the amino acid sequence of SEQ ID NO: 33; and VH FR4 having the amino acid sequence of SEQ ID NO: 59;
A VH FR1 having the amino acid sequence of SEQ ID NO: 60; a VH CDR1 having an amino acid sequence selected from SEQ ID NOs: 11 and 31; a VH FR2 having an amino acid sequence of SEQ ID NO: 61; and an amino acid sequence selected from SEQ ID NOs: 12 and 32 VH CDR2 having the amino acid sequence of SEQ ID NO: 62; VH CDR3 having an amino acid sequence selected from SEQ ID NOs: 13 and 33; and VH FR4 having the amino acid sequence of SEQ ID NO: 63;
VH FR1 having the amino acid sequence of SEQ ID NO: 60; VH CDR1 having the amino acid sequence of SEQ ID NO: 11; VH FR2 having the amino acid sequence of SEQ ID NO: 61; VH CDR2 having the amino acid sequence of SEQ ID NO: 12; VH FR3 having the amino acid sequence of SEQ ID NO: 13; and VH FR4 having the amino acid sequence of SEQ ID NO: 63;
VH FR1 having the amino acid sequence of SEQ ID NO: 60; VH CDR1 having the amino acid sequence of SEQ ID NO: 31; VH FR2 having the amino acid sequence of SEQ ID NO: 61; VH CDR2 having the amino acid sequence of SEQ ID NO: 32; VH FR3 having the amino acid sequence of SEQ ID NO: 33; and VH FR4 having the amino acid sequence of SEQ ID NO: 63;
VH FR1 having the amino acid sequence of SEQ ID NO: 64; VH CDR1 having an amino acid sequence selected from SEQ ID NO: 11 and 31; VH FR2 having the amino acid sequence of SEQ ID NO: 65; amino acid sequence selected from SEQ ID NO: 12 and 32 VH CDR2 having the amino acid sequence of SEQ ID NO: 66; VH CDR3 having an amino acid sequence selected from SEQ ID NOs: 13 and 33; and VH FR4 having the amino acid sequence of SEQ ID NO: 67;
VH FR1 having the amino acid sequence of SEQ ID NO: 64; VH CDR1 having the amino acid sequence of SEQ ID NO: 11; VH FR2 having the amino acid sequence of SEQ ID NO: 65; VH CDR2 having the amino acid sequence of SEQ ID NO: 12; VH FR3 having the amino acid sequence of SEQ ID NO: 13; and VH FR4 having the amino acid sequence of SEQ ID NO: 67; or
VH FR1 having the amino acid sequence of SEQ ID NO: 64; VH CDR1 having the amino acid sequence of SEQ ID NO: 31; VH FR2 having the amino acid sequence of SEQ ID NO: 65; VH CDR2 having the amino acid sequence of SEQ ID NO: 32; VH FR3 having the amino acid sequence of SEQ ID NO: 33; and VH FR4 having the amino acid sequence of SEQ ID NO: 67
It comprises an antibody VH region comprising the isolated antibody or antigen-binding fragment thereof. A VH FR1 having an amino acid sequence of SEQ ID NO: 64; a VH CDR1 having an amino acid sequence selected from SEQ ID NOs: 1 and 21; a VH FR2 having an amino acid sequence of SEQ ID NO: 65; an amino acid sequence selected from SEQ ID NOs: 2 and 22 An antibody VH region comprising: a VH CDR2 having an amino acid sequence of SEQ ID NO: 66; a VH CDR3 having an amino acid sequence selected from SEQ ID NOs: 3 and 23; and a VH FR4 having an amino acid sequence of SEQ ID NO: 67; VL FR1 having an amino acid sequence of No. 76; VL CDR1 having an amino acid sequence selected from SEQ ID Nos. 4 and 24; VL FR2 having an amino acid sequence of SEQ ID No. 77; having an amino acid sequence selected from SEQ ID Nos. 5 and 25 VL CDR2; SEQ ID NO: 78 VL FR3 having the amino acid sequence; antibody VL region comprising the VL FR4 having an amino acid sequence of and SEQ ID NO: 79;; VL CDR3 having an amino acid sequence selected from SEQ ID NO: 6 and 26 or
VH FR1 having the amino acid sequence of SEQ ID NO: 64; VH CDR1 having the amino acid sequence of SEQ ID NO: 1; VH FR2 having the amino acid sequence of SEQ ID NO: 65; VH CDR2 having the amino acid sequence of SEQ ID NO: 2; An antibody VH region comprising: VH CDR3 having the amino acid sequence of SEQ ID NO: 3; and VH FR4 having the amino acid sequence of SEQ ID NO: 67; VL FR1 having the amino acid sequence of SEQ ID NO: 76; VL CDR1 having the sequence: VL FR2 having the amino acid sequence of SEQ ID NO: 77; VL CDR2 having the amino acid sequence of SEQ ID NO: 5; VL FR3 having the amino acid sequence of SEQ ID NO: 78; VL CDR3 having the amino acid sequence of SEQ ID NO: 6; And the amino acid sequence of SEQ ID NO: 79 An antibody VL region comprising VL FR4 having a row; or
VH FR1 having the amino acid sequence of SEQ ID NO: 64; VH CDR1 having the amino acid sequence of SEQ ID NO: 21; VH FR2 having the amino acid sequence of SEQ ID NO: 65; VH CDR2 having the amino acid sequence of SEQ ID NO: 22; An antibody VH region comprising: a VH CDR3 having the amino acid sequence of SEQ ID NO: 23; and a VH FR4 having an amino acid sequence of SEQ ID NO: 67; a VL FR1 having the amino acid sequence of SEQ ID NO: 76; an amino acid of SEQ ID NO: 24 VL CDR1 having the sequence: VL FR2 having the amino acid sequence of SEQ ID NO: 77; VL CDR2 having the amino acid sequence of SEQ ID NO: 25; VL FR3 having the amino acid sequence of SEQ ID NO: 78; VL CDR3 having the amino acid sequence of SEQ ID NO: 26; And SEQ ID NO: 79 Comprising an antibody VL region <br/> comprising VL FR4 having an amino acid sequence, isolated antibody or antigen-binding fragment thereof according to any one of the 請 Motomeko 1 17. Chimeric antibody molecules or antigen-binding fragment der thereof, is, if desired, the variable region amino acid sequence of the antibody according to any one of claims 1 18, and a human constant region amino acid sequence; and / Or
Lacks complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC); and / or
Human LAG-3 protein (or human LAG-3Ig protein) is determined by, for example, Biacore analysis, 100 pM or less, 90 pM or less, 80 pM or less, 70 pM or less, 60 pM or less, 50 pM or less, 40 pM or less. Bind with a dissociation constant (K _D ) of 30 pM or less, or 25 pM or less ; and / or
An agonistic anti-LAG-3 antibody or antigen-binding fragment thereof; and / or
Does not bind to the 30 amino acid extra loop sequence (SEQ ID NO: 40) of the first N-terminal D1 domain of the human LAG-3 protein;
The isolated antibody or antigen-binding fragment thereof according to any one of claims 1 to 18 .   VL FR1 having an amino acid sequence of SEQ ID NO: 76; VL CDR1 having an amino acid sequence selected from SEQ ID NOs: 4 and 24; VL FR2 having an amino acid sequence of SEQ ID NO: 77; and an amino acid sequence selected from SEQ ID NOs: 5 and 25 An antibody VL region comprising: a VL CDR3 having an amino acid sequence selected from SEQ ID NOs: 6 and 26; and a VL FR4 having an amino acid sequence of SEQ ID NO: 79;
  VH FR1 having an amino acid sequence of SEQ ID NO: 52; VH CDR1 having an amino acid sequence selected from SEQ ID NOs: 1 and 21; VH FR2 having an amino acid sequence of SEQ ID NO: 53; amino acid sequences selected from SEQ ID NOs: 2 and 22 An antibody VH region comprising: a VH CDR2 having VH FR3 having an amino acid sequence of SEQ ID NO: 54; a VH CDR3 having an amino acid sequence selected from SEQ ID NOs: 3 and 23; and a VH FR4 having an amino acid sequence of SEQ ID NO: 55
The isolated antibody according to any one of claims 1 to 8, 15, 16 (i), 16 (ii), 16 (iii), 17 (i), 17 (ii) or 19, or An antigen-binding fragment, or
  A modified version of the antibody or antigen-binding fragment thereof comprising one or more amino acid substitutions that eliminate glycosylation at this site, resulting in the loss of the glycosylation site of one or more variable region frameworks.   VL FR1 having an amino acid sequence of SEQ ID NO: 76; VL CDR1 having an amino acid sequence selected from SEQ ID NOs: 4 and 24; VL FR2 having an amino acid sequence of SEQ ID NO: 77; and an amino acid sequence selected from SEQ ID NOs: 5 and 25 An antibody VL region comprising: a VL CDR3 having an amino acid sequence selected from SEQ ID NOs: 6 and 26; and a VL FR4 having an amino acid sequence of SEQ ID NO: 79;
  VH CDR1, VH CDR2, and VH CDR3, wherein the VH CDR1 has an amino acid sequence selected from SEQ ID NOs: 1 and 21, and the VH CDR2 has an amino acid sequence selected from SEQ ID NOs: 2 and 22 Wherein the VH CDR3 comprises a VH CDR1, VH CDR2 and VH CDR3 having an amino acid sequence selected from SEQ ID NOs: 3 and 23, and a humanized heavy chain of any one of SEQ ID NOs: 52-67 Antibody VH region including framework region
The isolated antibody according to any one of claims 1 to 8, 15, 16 (i), 16 (ii), 16 (iii), 17 (i), 17 (ii) or 19, or Antigen binding fragment. The nucleotide sequences encoding the antibody or antigen-binding fragment thereof as set forth 請 Motomeko 1 in any one of 21; or
A nucleotide sequence of any of SEQ ID NO: 9, 10, 19, or 20 or a nucleotide sequence that is at least 80% identical to a nucleotide sequence of any of SEQ ID NO: 9, 10, 19, or 20 <br> A nucleic acid comprising A recombinant vector comprising the nucleic acid according to claim 22 . A recombinant cell comprising the nucleic acid according to claim 22 or the recombinant vector according to claim 23 . A pharmaceutical composition comprising the isolated antibody or antigen-binding fragment thereof according to any one of claims 1 to 21 , and a pharmaceutically acceptable carrier, excipient or diluent. 26. A composition comprising the isolated antibody or antigen-binding fragment thereof according to any one of claims 1 to 21 or a pharmaceutical composition according to claim 25 , for use as a medicament. 26. A composition comprising an isolated antibody or antigen-binding fragment thereof according to any one of claims 1 to 21 or a pharmaceutical composition according to claim 25 for use in the treatment of a T cell mediated immune disorder. object. 26. In the manufacture of a medicament for treating a T cell mediated immune disorder, an isolated antibody or antigen-binding fragment thereof according to any one of claims 1 to 21 or a pharmaceutical composition according to claim 25 in the manufacture of a medicament for treating a T cell mediated immune disorder. use. A composition comprising an isolated antibody or antigen-binding fragment thereof for use according to claim 27, or a use according to claim 28, comprising:
The T-mediated immune disorder is an inflammatory disease or autoimmune disorder; or
The T cell-mediated immune disorder is arthritis, rheumatoid arthritis, asthma, COPD, pelvic inflammatory disease, Alzheimer's disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, Peroni disease, celiac disease, gallbladder disease, hair follicle Disease, peritonitis, psoriasis, vasculitis, surgical adhesions, stroke, type I diabetes, Lyme disease, meningoencephalitis, autoimmune uveitis; multiple sclerosis, lupus (such as systemic lupus erythematosus), and Guillain- Central and peripheral nervous system immune-mediated inflammatory disorders such as Valley syndrome; atopic dermatitis, autoimmune hepatitis, fibroalveolaritis, Graves disease, IgA nephropathy, idiopathic thrombocytopenic purpura, Meniere's disease , Pemphigus, primary biliary cirrhosis, sarcoidosis, scleroderma, Wegener's granulomatosis, other autoimmune disorders, pancreatitis, trauma (surgical trauma), graft-versus-host disease Graft rejection; heart disease including ischemic diseases such as myocardial infarction and atherosclerosis; intravascular coagulation, bone resorption, osteoporosis, osteoarthritis, periodontitis, and hypochlorhydia, or maternal-infant immunity A composition or use selected from the group consisting of infertility associated with lack of tolerance .